SURGICAL PATIENTS AT RISK FOR RENAL FAILURE

Dr.K.T.Ramadas Professor & Head, Department of Anaesthesiology Govt.Medical College, Thrissur

Introduction: Acute Kidney Injury (AKI), formerly known as Acute Renal Failure is associated with increased morbidity, mortality, duration of hospital stay, and health care cost. Perioperative acute kidney injury is common but poorly recognized and managed. Evidence shows that even small transient rise in serum creatinine are associated with an increase of risk of death. Appropriate perioperative strategies are required to protect renal function to optimize patient outcome. Perioperative ARF accounts for 20-25% of cases of hospital-acquired renal failure. The incidence varies between 1 and 25% depending on the type of surgery and on the definition of renal failure. Renal dysfunction after surgery is often associated with multiple organ dysfunction syndrome (MODS) and may result in a mortality of upto 60%. It is also associated with a high risk of infection, prolonged intensive care unit (ICU) and hospital stay. Progression to chronic renal failure (CRF), and dialysis dependent end-stage renal disease (ESRD). The chance of full recovery from an episode of ARF in the surgical setting is only 15%, many patients progress to develop varying degrees of chronic renal dysfunction.

Patients undergoing cardiac and vascular surgery are at particular risk of developing ARF. ARF related to major surgery in patient with significant co-morbidity commonly results in a poor outcome. ARF after open abdominal aortic surgery is also associated with a high mortality. A large multi-centre cohort study demonstrated that ARF requiring dialysis occurred in 1.1% of cardiac surgical patients and was associated with an operative mortality of 63.7%. Causes of hospital-acquired acute renal failure : Associated Frequency and Mortality Cause Decreased renal perfusion Medications Radiographic contrast media Surgery Sepsis Post-liver Transplant Post-heart Transplant Obstruction Hepatorenal syndrome Rhabdomyolysis Frequency 39% 16% 11% 9% 6.5% <5% <5% <5% <1% <1% Mortality 13.6% 15% 14% 2.8% 76% 28.6% 35% 28.6% 71.4%

(Adapted from Nash OK, Hafeez A, Hou S. Hospital acquired renal insufficiency. Am J Kidney Dis. 2002; 3: 930-936).

Definition of Acute Kidney Injury (AKI) AKI is a sudden and usually reversible decrease in the glomerular filtration rate (GFR) occurring over a period of hours to days. AKI may occur in patients with previously normal renal function or patients with Chronic Kidney Disease (CKD). The Acute Dialysis Quality Initiative (ADQI) has developed the Risk,
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Injury, Failure, Loss, End-State Kidney Disease (RIFLE) classification of ARF because of the lack of universal definition of ARF. The RIFLE criteria have a high sensitivity for the early diagnosis of AKI and should allow detection of patients at risk to develop AKI as well as those patients with established AKI. RIFLE stands for 3 severity classes and 2 outcome classes. Severity grades are defined on the basis of serum creatinine or urine output whereas outcome criteria are based on the duration of loss of kidney function. RIFLE Staging for Acute Kidney Injury
Stage GFR Criteria Urine Output Criteria(UO)

Risk

Increased serum creatinine x 1.5 or UO <0.5ml/kg/hr x 6hrs GFR decrease >25% or absolute increase in S.Cr. of 0.3mg/dl

Injury

Increased S.Cr x 2 or GFR decrease UO <0.5ml/kg/hr x 12hrs >50%

Failure

Increased S.Cr x 3 or GFR decrease UO <0.3ml/kg/hr x 24hrs >75% or S.Cr >4mg/dl or Anuria x 12hrs

Loss

Persistent AKI = Complete loss of kidney function >4 weeks (i.e.

dialysis dependence for 4 weeks) End kidney disease (ESKD) stage End Stage Kidney Disease (i.e. dialysis dependence for >3 months)

(GFR : Glomerular Filtration Rate, S.Cr: Serum creatinine, UO: Urine output)

The Acute Kidney Injury Network (AKIN) has defined AKI as an abrupt (within 48 hours) reduction in kidney function. AKIN staging for Acute Kidney Injury:
Stage Serum Creatinine (S.Cr) Criteria Urine Output Criteria(UO)

Increase

in

serum

creatinine <0.5ml/kg/hr > 6hrs

>0.3mg/dl or >150%-200% from base line 2 Increase in S.Cr > 200% - 300% <0.5ml/kg/hr for > 12hrs 3 Increase in S.Cr >300% from <0.3ml/kg/hr >24hrs or

baseline or S.Cr > 4mg% with an Anuria for >12hrs acute increase of atleast 0.5mg/dl or receiving renal replacement therapy

KDIGO (Kidney Disease : Improving Global Outcomes) AKI is common, harmful and potentially treatable. Even a minute acute reduction in kidney function has an adverse prognosis. Early detection and treatment of AKI may improve outcome. Two definitions based on serum

creatinine and urine output (RIFLE and AKIN) have been proposed and validated. Thre is a need for a single definition for practice, research and public health. AKI defined as any of the following: Increase in S.Cr by > 0.3mg/dl within 48hrs; OR Increase in S.Cr x 1.5times baseline, which is known or presumed to have occurred within the prior 7 days OR Urine volume <0.5ml/Kg/hr for 6 hrs
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Staging of AKI for Severity

Stage Serum Creatinine (S.Cr) Urine Output Criteria(UO)

1.5-1.9 times baseline OR > 0.3mg/dl

<0.5ml/kg/hr for 6-12hrs

2-2.9 times baseline

<0.5ml/kg/hr for > 12hrs

3 times baseline or increase in

<0.3ml/kg/hr for >24hrs or

S.Cr to >4mg% or initiation of renal Anuria for >12hrs replacement therapy or in patients

<18years, a decrease in a GFR to <35ml/min/1.73m2

PATHOPHYSIOLOGY: Along with maintaining fluid homeostasis, one of the main functions of the kidney is to excrete waste products, water soluble medications and water soluble products of metabolism. It does this by filtering the blood via its functional units, the nephrons, utilizing active and passive processes including ultrafiltration, followed by resorption and tubular secretion, depending on the solute. In healthy adults, renal blood flow (RBF) is approximately 1.2-1.3 l/min of blood or 20% of cardiac output. The GFR is the volume of plasma filtered per unit time by all the glomeruli of the kidneys. The GFR in the average 70kg man is 125ml/min or approximately 10% of RBF. Almost all (99%) of this filtrate is normally reabsorbed. Renal autoregulation is an intrinsic property of the kidney independent of neurohormonal stimulation which allows GFR to be preserved at a constant rate at mean arterial blood pressures of between 70-170mmHg. This is possible due to changes in local vascular resistance of the afferent and efferent
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arterioles secondary to renal vasoactive substances such as norepinephrine, epinephrine, acetyl choline, angiotensin, prostaglandins and kinins. Autoregulation is prevented by drugs that paralyse smooth muscle. Autoregulation occurs at the level of afferent arteriole, where nitric oxide (NO) mediates the smooth muscle of response to stretch. At low perfusion pressures, angiotensin II constricts the efferent arteriole, thus maintaining filtration pressure across the glomerular membrane. Drugs that interfere with these mediators include non-steroidal antiinflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) inhibitors, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers. These drugs can precipitate renal failure during hypoperfusion. Classification of AKI: AKI can be classified as pre-renal, renal or post-renal dysfunction. Pre-renal dysfunction is the most common in surgical patients. Surgery itself involves many risk factors contributing to this. Patients who are shocked, or with probable atheromatous disease are at high risk of developing AKI.

Acute Renal Failure: - Pre-renal causes (55%) - Intrinsic renal causes (40%) - Post-renal causes (5%) Pre-renal causes: Hypovolemia, Hypotension, Renal Artery stenosis Intrinsic renal causes: Glomerular disease (inflammation or thrombosis), tubular injury (ischaemia or toxins), interstitial nephritis, vascular disease (inflammation, occlusion which can be thrombosis or embolism) Post-renal causes: BPH, Prostate/Cervical cancer, Bil.ureteric obstruction.

Pre-renal Azotemia: Pre-renal azotemia is a fall in the GFR due to reduced renal perfusion in which minimal or no structural or cellular damage to the kidney occurs. It may be secondary to true intravascular volume depletion or arterial underfilling from a decrease in cardiac output or arterial vasodilatation.

CAUSES OF PRE-RENAL ARF

ECF volume

ECF volume with arterial underfilling

Cardiac output Renal Losses Third space losses Gastrointestinal losses

Systemic arterial vasodilatation

Cirrhosis

Sepsis

Myocardial infarction

Pericardial tamponade, Constrictive pericarditis

Total intravascular volume depletion: Renal fluid loss: - Excessive diuresis (diuretics) - Osmotic diuresis (eg: glycosuria) GI fluid loss: Vomiting, diarrhoea and nasogastric tube drainage

Skin fluid loss: Burns, excessive sweating Third space loss: Peritonitis, pancreatitis, SIRS, Profound hypoalbuminemia Effective volume depletion from arterial underfilling: Arterial underfilling is a state in which intravascular volume is actually normal (or even increased), but circulating factors are inadequate to maintain renal perfusion pressure. Underfilling may be due to either a decrease in cardiac output or arterial vasodilatation and may occur in a number of clinical settings. Reduced cardiac output: - Congestive heart failure (CHF) - Cardiogenic shock (acute MI) - Pericardial effusion with tamponade - Massive pulmonary embolism Peripheral Vasodilatation: - Sepsis - Antihypertensive medication - Anaphylaxis - Anaesthesia - Cirrhosis and other liver diseases Intrinsic azotemia is characterized by disease affecting renal parenchyma itself, the causes of which can be divided into the portion of the kidney affected. Vasculature: Vessels at all levels of the renal vascular system may cause AKI. Large vessels (atheroembolic disease, renal artery stenosis, aortic disease, small vessel (vasculitis) and veins (renal vein thrombosis) may all cause AKI. Tubular: Tubular injury may be due to ischaemia or toxins Renal hypoperfusion when prolonged or severe, can cause acute tubular necrosis. ATN may also result
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from medications (eg.aminoglycosides, radiographic contrast) or may be due to endogenous (crystals, myoglobin, hemoglobin) or exogenous (radiographic contrast) toxins. Causes of Renal Ischemia: Shock, Hemorrhage, Trauma, Gram-negative sepsis, pancreatitis,

hypotension from any cause. Glomerular either Nephrotic or Nephritic, Nephritic glomerular disorders (glomerulonephritis) are characterized by hematuria or proteinuria (typically 1-2 gm in 24hrs). Nephrotic glomerular disorders are characterized by large proteinuria (more than 3gm in 24 hours) and minimal hematuria. Nephritic disorders are more commonly associated with AKI than nephrotic disorders. Interstitial: More commonly due to drug hypersensitivity, but may also be a consequence of infections or systemic disease (systemic lupus erythematosus). Various drugs are involved like antibiotics (cephalosporins, ciprofloxacin, rifampicin, sulfonamide). Diuretics (Furosemide, Thiazides), NSAIDs,

Anticonvulsants (phenytoin, carbamazepine). Postrenal azotemia: is due to obstruction (intrinsic or extrinsic) of the urinary tract.l AKI due to post-renal causes must involve both kidneys (unless the patient has only a solitary kidney or baseline poor renal function). The most common causes are the prostate (BPH or Prostatic carcinoma), cervix (carcinoma), blocked catheters,bilateral stones and retroperitoneal fibrosis. Easily diagnosed by ultrasonography. Urine and serum diagnostic indices for differentiating prerenal and renal azotemia: Measure Renal blood flow (ml/min) Urine output (ml/kg/hr) Prerenal Reduced <0.5 Renal Reduced/Normal

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Creatinine clearance (ml/min) Urine specific gravity Urine osmolality (mOsm/Kg) Urinary sodium (mEq/litre) Fractional excretion of sodium (FENa) BUN; Creatinine

Reduced >1.020 >500 <20 <1 <20:1

Reduced <1.010 <350 >40 >1 <10:1

FENa = PCr/UCr PNa/UNa (PCr Plasma creatinine, U Cr- Urine Creatinine; PNa : Plasma Sodium; UNa: Urine Sodium); Serum Na and Urine Na in mmol/litre and creatinine in

mol/litre.)
Markers for AKI and GFR: 1) Serum Creatinine: Normal serum creatinine is 0.6-1.2mg/dl and is the most commonly used parameter to assess renal function. It is the end product of skeletal muscle metabolism and is present at a fairly constant concentration in the plasma. It is freely filtered, not reabsorbed and small amounts can be secreted. When GFR decreases by more than 50%, creatinine exceeds its ability to be filtered and levels will rise in the plasma. Therefore a rising serum creatinine is indicative of renal dysfunction. The trend of serum creatinine is more important than absolute value as concentration is related to body skeletal mass. Other factors that may affect serum creatinine include drugs, diet, BMI and other organ dysfunction. The following graph demonstrates the relationship between creatinine and GFR. This graph demonstrates that creatinine only begins to increase after more than 50% of
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renal nephron function has been lost signifying that a rise in creatinine is critically important.

Relationship between plasma creatinine and GFR

2) Blood Urea/BUN: Urea, a waste product produced in the liver, is a less reliable indicator of renal function. It is freely filtered, but also reabsorbed. It is a product of protein metabolism and production depends on protein intake, protein catabolism and variable rates of renal reabsorption. Urea absorption is increased in states of dehydration as it is taken up via aqua porins in response to increased vasopressin secretion. Normal BUN is 8-18mg/dl. An increase in BUN typically accompanies a rise in serum creatinine in the setting of AKI. BUN

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can rise without a rise in creatinine, resulting in a BUN to serum creatinine ratio that is greater than 20. Cystatin C: It is a protein produced by all nucleated cells. It is freely filtered by the glomerulus, completly reabsorbed by the proximal tubules, and is not secreted by the renal tubules. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise. Serum levels of cystatin C are a more precise test of kidney function than serum creatinine levels. Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine. It has been reported to increase about 1-2 days earlier than serum creatinine. It is said to be diagnostically superior to serum creatinine, especially in patients with liver cirrhosis.

Biomarkers of AKI: A biomarker that is released into the blood or urine by the injury kidney and is analogous to the troponin release by injured myocardial cells after myocardial ischaemia/infarction, is a more sensitive and specific marker of AKI than BUN and serum creatinine. Urine or blood Neutrophil Gelatinase-Associated Lipocaline (NGAL), urinary interleukin-18 (IL-18) and Kidney injury molecule-1 have been found to increase 1-2 days before serum creatinine rise in patients with ischaemic AKI. This can allow early detection of AKI and better chances of reversibility of AKI. NGAL: Also called lipocalin-2 or siderocalin. It is involved in renal morphogenesis, such as induction of repair and reepithelialisation. It has been shown to be elevated in the plasma and urine of animal models of ischaemia and nephrotoxic acute kidney injury. Urinary NGAL expression has been suggested as an early marker of AKI in children. NGAL level peaks within 2-4 hours following AKI.
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Interleukin 18 (IL-18): Proinflammatory cytokine IL-18 rises prior to serum creatinine in human AKI and peaks around 12th hour after AKI. It is formed in the proximal tubules and detected in the urine. It can be used for early diagnosis of AKI and predict mortality. Patients with ATN has significantly higher levels of IL18 in their urine than did other forms of kidney disease. Higher urinary levels of IL-18 in patients of delayed graft function after post-transplantation compared to immediate graft function. Kidney Injury Molecule (KIM-1) It is a recently discovered transmembrane tubular protein in urine of patients of acute kidney injury and chronic kidney disease. Many studies indicate that KIM-1 is a sensitive and specific marker of kidney injury as well as predictor of prognosis. It is not normally expressed in normal kidney but specifically expressed in injured proximal tubular cells. This expression persists until damaged cells have completely recovered. Urinary KIM-1 is closely related to tissue KIM-1 and closely related with severity of renal damage. Quantification of urinary KIM-1 is likely to be non-invasive and sensitive method for the evaluation of kidney injury and monitoring the therapeutic effects of kidney injury. Sodium / Hydrogen Exchanger Isoform 3 (NHE3): Most abundant apical membrane sodium transporter in the proximal tubules. In one study it has been shown that urinary NHE-3 is a better gauge than fractional excretion of sodium (FENa) in distinguishing pre-renal versus intrinsic kidney failure. Risk factors for perioperative AKI: By recognizing risk factors, patients at risk of AKI perioperatively can be identified. The incidence of AKI is increasing because of the increasing age of the surgical population and the performance of more complex surgery. Risk Factors for Perioperative Acute Renal Failure

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Preoperative Factors Chronic Disease Advanced age Female sex Chronic kidney disease Diabetes Chronic cardiac failure Aortic and peripheral vascular disease Chronic liver disease Genetic predisposition

Intraoperative Factors Type of surgery Cardiac Aortic Peripheral vascular Non-renal solid organ Transplantation Biliary tract and hepatic Surgery Urogenital surgery Complicated obstetrics

Postoperative Factors Acute conditions Acute cardiac dysfunction Hemorrhage Hypovolemia Sepsis Rhabdomyolysis Intraabdominal Hypertension Multiple organ Dysfunction syndrome (MODS) Drug nephrotoxicity

Acute Conditions

Cardiac Surgery:

Hypovolemia/Hypotension Preexisting renal Dehydration Sepsis Preoperative IABP Insufficiency Emergency surgery Combined procedures Previous cardiac surgery Multiple organ dysfunction syndrome Drug Nephrotoxicity Prolonged CPB time MAJOR TRAUMA Direct renal trauma Haemorrhagic shock Massive blood transfusion Elevated intraabdominal pressure Rhabdomyolysis Sepsis and MODS

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Vascular Surgery Preexisting renal Insufficiency Intraoperative Radiocontrast Sepsis Aortic cross clamp -Direct renal ischaemia -Myocardial ischaemia -Low cardiac output -Declamping hypotension Renal artery atheromatous embolisation Ruptured aortic aneurysm

Optimising Management:

The identification of high-risk patients and the

implementation of prophylactic measure are the goals of perioperative renal protection. Strategies to reduce the occurrence of renal injury in patients without evidence of acute renal dysfunction are referred to as primary prevention. The avoidance of additional renal injury in the setting of established acute renal dysfunction is termed secondary prevention. Intravascular volume expansion:

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Perioperative hypovolemia should be rapidly corrected by volume expansion with IV fluids, whether occurring before, during or after surgery. A large multicentre trial of fluid resuscitation in critically ill patients found no difference between albumin and 0.9% sodium chloride in terms of the risk of ARF. Albumin and gelatin appear to be safe in patients with normal function. The safety of hydroxyl ethyl starch solutions in the setting of established renal impairment has not been clarified. In the absence of hemorrhagic shock, suggestion is to use isotonic crystalloids rather than colloids (albumin or starch) as initial management for expansion of intravascular volume in patients at risk for AKI or with AKI.

Vasopressors: Persistent hypotension despite ongoing aggressive fluid resuscitation or after optimization of intravascular volume in patients with shock, places patients at risk for development of AKI. In the setting of vasomotor paralysis, preservation or improvement of renal perfusion can only be achieved through use of systemic vasopressors once intravascular volume has been restored. Norepinephrine is preferred to dopamine as dopamine is associated with more arrhythmias and adverse events. Vasopressin is gaining popularity in the treatment of shock refractory to norepinephrine. Recommendation regarding use of vasopressors is to use it in conjunction with fluids in patients with vasomotor shock with, or at risk for, AKI. Protocolized Hemodynamic Management:
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Suggestion is to use protocol-based management of hemodynamic and oxygenation parameters to prevent development or worsening AKI in high risk patients in the perioperative setting or in patients with septic shock. Goal directed therapy is defined as hemodynamic monitoring with defined target values and with a time limit to reach these stated goals. These protocols have the potential to reduce the risk of AKI following major surgical procedures in high risk patients (eg: Age >60yrs, emergent surgery, elevated ASA score, preoperative comorbid illnesses). Early recognition of septic shock initiates a protocol of resuscitation with the goal of reestablishing tissue perfusion in patients within 6 hours of diagnosis. The physiologic goals are: 1) return of Mean arterial blood pressure 65mm Hg; 2) Central venous pressure between 8-12mmHg; 3) Improvement in blood lactate levels; 4) Central venous oxygen saturation (SCvO2) >70%; and 5) Urine output > 0.5ml/kg/hr. The basic strategy of goal-directed therapy to prevent AKI in the perioperative period is based on protocols that avoid hypotension, optimize oxygen delivery, careful fluid management, vasopressors when indicated and inotropic agents and blood products if needed. Protocols for resuscitation in the setting of septic shock and high risk surgery appear to be superior to no protocol. Glycemic control in critical illness; Renal effects and outcomes: In critically ill patients, suggestion is to use insulin therapy targeting plasma glucose 110-149mg/dl. Tight glycemic control is frequently used in patients at risk of AKI, and in the management of those who develop AKI. It has been proposed that tight glycemic control can reduce the incidence and severity of AKI. Use of diuretics in AKI:
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Diuretics are frequently used in patients at risk of AKI, and in the management of those who develop AKI. Since fluid overload is one of the major symptoms of AKI, diuretics are often used for patients with AKI to facilitate fluid management. It is used with the presumption that oliguric AKI has a worse prognosis than non oliguric AKI and physicians often prescribe diuretics to convert oliguric AKI to nonoliguric AKI. Also used thinking that diuretics have potentially renoprotective effects that might prevent development of AKI and hasten its recovery. Diuretics can also be harmful, by reducing the circulating volume excessively and adding a pre-renal insult, worsening established AKI. It is essential to evaluate usefulness of diuretics to improve outcome of patients with AKI, not just for fluid management. Recommendation is not to use diuretics to prevent AKI, suggestion is not to use diuretics to treat AKI, except in the management of volume overload. Mannitol: Mannitol acts as a osmotic diuretic to increase filtrate volume and subsequent tubular flow. Within the tubule, mannitol decreases tubular cell dimensions (through dehydration), increases tubular diameter, and decreases tubular resistance. It may act as a free radical scavenger, thus making it attractive in ischaemia-reperfusion injury. In human trials, the use of mannitol may suggest a renoprotective effect in renal transplantation. It is highly probable that mannitol does not convey additional beneficial effects beyond adequate hydration on the incidence of AKI. Furosemide: Furosemide, by inhibiting sodium absorption in the medullary portion of the loop of Henle, causes diuresis and natriuresis. It potentially limits any worsening
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of medullary hypoxia by decreasing tubular cell workload and thus oxygen consumption. However, there is little literature supporting it as a renoprotective agent. Dopamine: Dopamine was once commonly used for renal protection in the critically ill. With multiple negative studies, its use has been abandoned by most. Low dose dopamine administration (1-5mcg/kg/min) to healthy individual cause renal vasodilatation, natriuresis and increased GFR. Recent data suggest that renal vasodilatory effect of dopamine found in healthy population is not preserved in patients with AKI. Using ultrasound Doppler, found that dopamine significantly increased renal vascular resistance in AKI patients. There is also limited evidence that use of dopamine to prevent or treat AKI can cause harm. Low dose directly vasodilates vessels in the cortex and is directly vasodilates vessels in the inner medulla. This causes a redistribution of blood away from the outermedulla, which contains energy dependent Na+/K+-

ATPase channels of the medullary thick ascending limb. Natriuretic effect of low dose causes an increased solute load to the distal tubular cells, which may actually increase oxygen consumption and thereby increase the risk of ischaemia. Low dose dopamine can induce tachycardia, dysarrhythmias and myocardial ischaemia. It can produce mesenteric ischaemia which is harmful in the critical care and intraoperative setting, because it compromises the mucosal lining and reduces perfusion for anastomoses. It can cause panhypopituitarism, including suppression of prolactin, growth hormone and thyrotropin. Growth hormone suppression contributes to a negative nitrogen balance in critical illness, and prolactin suppression induces a transient decrease in T-cell function. So no role for low dose dopamine to prevent or treat AKI.
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Fenoldopam mesylate: Pure dopamine type-1 receptor agonist that has similar hemodynamic renal effects as low dose dopamine, without systemic or beta adrenergic stimulation. Suggestion is not to use fenoldopam to prevent or treat AKI. Natriuretic Peptides: Several natriuretic peptides are in clinical use or in development for treatment of congestive heart failure or renal dysfunction, and could potentially be useful to prevent or treat AKI. Current suggestion is not to use atrial natriuretic peptides to prevent or treat AKI. Growth factor intervention: Recovery from AKI involves increased expression of various growth factors acting via autocrine, paracrine and endocrine mechanisms. Experimental studies have yielded promising results with individual growth factors like insulin like growth factor-1 (IGF-1), hepatic growth factors and erythropoietin. IGF-1 is a peptide with renal vasodilatory mitogenic and anabolic properties. Recommendation is not to use recombinant human IGF-1 to prevent or treat AKI. Recent animal studies suggest a potential clinical benefit of erythropoietin in AKI. The renoprotective action of erythropoietin may be related to pleomorphic properties including antiapoptotic and antioxidative effects, stimulation of cell proliferation and stem cell mobilization. Adenosine Receptor Antagonists: Used to decrease tubuloglomerular feed-back, mediated vasoconstriction and increase RBF and GFR in AKI. Adenosine receptor antagonists tried in three clinical syndromes with increased risk of AKI, Perinatal asphyxia, radiocontrast exposure and cardiorenal syndrome. Theophylline is a nonselective adenosine receptor antagonist. Suggestion is that a single dose of theophylline may be given in neonates with severe perinatal asphyxia, who are at high risk of AKI.
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N-Acetyl Cysteine (NAC): Current suggestion is not to use NAC to prevent AKI in critically ill patients with hypotension. NAC is a modified form of L-cysteine, an amino acid that is a precursor to reduced glutathione that can regenerate glutathione stores. It is a potent antioxidant that scavenges oxygen free radicals in the body. It also has a vasodilatory properties derived from enhanced nitric oxide (NO) availability. Recommendation is not to use oral or IV NAC for prevention of post surgical AKI. Suggestion is to use oral NAC, together with IV isotonic crystalloids in patients at increased risk of CI-AKI. Medicines Management: i) Non-steroidal Anti-inflammatory Drugs (NSAIDs) These drugs can produce renal dysfunction and failure acute papillary necrosis, acute interstitial nephritis, decreased renal blood flow, decreased glomerular filtration rate, salt and water retention. They impair renal autoregulation by inhibiting prostaglandin mediated dilatation of the afferent glomerular arteriole, the purpose of which is to maintain renal blood flow in the face of systemic vasoconstriction, e.g. in hypovolemia. In normal, sodiumrepleted, well-hydrated individuals, the role of prostaglandins in the kidney is less important than in patients with abnormal renal function, hypovolemia or abnormal serum electrolytes, in whom local synthesis of vasodilating prostaglandins is important in maintaining renal homeostasis. Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB): These prevent the local action of bradykinins, which are responsible for constriction of the efferent glomerular arteriole, the purpose of which is to maintain glomerular perfusion pressure in renal autoregulation. It is suggested that

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ACEI or ARBs be stopped on the day of surgery for renal protection and to minimize the risk of hypotension with anaesthetic agents. Antibiotics: Renal tubular toxicity may occur at high concentration in aminoglycosides, eg.gentamycin. Acute interstitial nephritis can occur with certain antibiotics, eg:Penicillins, Cephalosporins and fluoroquinolones. Suggestion is not to use aminoglycosides for treatment of infections unless no suitable, less nephrotoxic, therapeutic alternatives are available.

Aminoglycosides should be used for as short a period of time as possible. In patients with normal kidney function in steady state, aminoglycosides are administered as a single dose daily rather than multiple dose daily treatment regimens. Suggest using topical or local applications of aminoglycosides rather than I.V.application where feasible and suitable. Contrast Induced AKI (CI-AKI) CI-AKI are frequent and occur in both ambulatory and hospitalized patients. The term CI-AKI is used for patients developing AKI secondary to intravascular radiocontrast media exposure. Contrast induced nephropathy is defined as a rise in S.Cr of >0.5mg/dl or a 25% increase from baseline value, assessed at 48 hours after a radiological procedure. Assess the risk for AKI, and in particular screen the pre-existing impairment of kidney function in all patients who are considered for a procedure that requires intravenous or intra arterial administration of iodinated contrast medium. Risk factors for CI-AKI: Risk factors include advanced age, chronic kidney disease, diabetes mellitus, hypertension, congestive heart failure, hypotension, hypovolemia, anaemia, intraarterial (rather than intravenous) injection of contrast agent, non-steroidal antiinflammatory drugs, high volume or high osmolality of the contrast agent, Cardiac

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surgery after contrast agent. Consider alternative imaging method in patients at increased risk for CI-AKI. Prevention of CI-AKI: Includes parenteral volume expansion, minimizing contrast media volume, use of low osmolar (iohexol) and isoosmolar (iodixanol) contrast media and administration of non-iodinated contrast media. Extracellular volume expansion at the time of radiocontrast media administration may serve to counteract both the intrarenal hemodynamic alterations and the direct tubulotoxic effects that play a role in the pathophysiology of CI-AKI. Neurohormonal effects of volume expansion that may attenuate radio contrast induced medullary hypoxia include suppression of vasopressin as well as inhibition of the renin-angiotensin axis; but an increase and synthesis of vasodilatory renal prostaglandins may also play a role. Volume expansion may also directly reduce cellular damage by dilution of the contrast medium, particularly in the medullary tubular segments. An effect of radio contrast media to increase tubular fluid viscosity may be diminished by intra vascular volume expansion. Present recommendation is IV volume expansion with either isotonic sodium chloride or sodium bicarbonate solution, rather than no IV expansion, in patients at increased risk for CI-AKI. Timing of Renal Replacement Therapy in AKI: The optimal timing of dialysis for AKI is not defined. In current practice, the decision to start RRT is based most often on clinical features of volume overload and biochemical features of solute imbalance (azotemia, hyperkalemia, severe acidosis). So initiate RRT emergently when life threatening changes in fluid, electrolyte and acid-base balance exist. Discontinue RRT when it is no longer
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required, either because intrinsic kidney function has recovered to the point that it is adequate to meet patient needs, or because RRT is no longer consistent with the goals of care. Urine output and Renal Protection: Intraoperative urine output is essential to good post operative renal outcome. Although it is true that the best monitor of intraoperative renal function is urine output, this is unfortunately true only in the sense that there is no other easily available monitoring of renal function in the operating room. Quality of urine produced is also important as quantity of urine produced. Decreased urine output may be due to either a kinked or misplaced Foley catheter or an unsuspected urinary tract injury in the surgical field. Delayed diagnosis of the kinked catheter and volume resuscitation will result in an over distended bladder and ultimately obstructive renal failure. In urinary tract injury, renal function is not affected. It has been frequently observed that patients undergoing laparoscopic surgery have lower-than-expected intraoperative urine output. Aggressive volume resuscitation in these patients may or may not increase urine output. In multiple studies in animal models, pneumoperitoneum of 15mm Hg or less reduces urine output but does not result in significant changes in ultrasound, pathologic or chemical indicators of renal function. The reduced urine output reflects a reversible non injurious physiologic consequence of pneumoperitoneum. Patients undergoing radical head and neck surgery have also been observed to have relative oliguria intraoperatively. New technologies such as continuous renal ultrasound and near infrared regional oximetry offer some hope of improving the monitoring of intra-operative renal function. Outcomes after AKI: 3 possible outcomes:
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1. Return to baseline renal function 2. Development of chronic kidney disease in previously normal kidneys 3. Accelerated progression of disease in patients with preexisting CKD (5 fold increased risk for end stage disease). Specific Surgeries: Cardiac and Vascular Surgery: Several factors are involved in the development of ARF: 1) Renal hypo-perfusion outside the limits of auto-regulatory reserve, particularly during cardiopulmonary bypass. 2) The systemic inflammatory response syndrome (SIRS) triggered by major surgery results in cell-mediated cytotoxic injury. 3) Renal embolic injury can exacerbate ATN. 4) Prolonged surgery produces hemolysis; renal excretion of haem derivatives may result in renal tubular injury. 5) Toxic injury from administration of nephrotoxic drugs including radiocontrast load. Endovascular aortic surgery is also associated with ARF because of the administration of large dose of contrast. 2) Abdominal Aortic Aneurysms: Renal function is impaired in about 10% of patients and this may be aggravated by hypovolemia and hypotension intra-operatively.Despite infra-renal application of the aortic cross clamp, renal blood flow may be reduced by about 40% with an increase of upto 75% in renal vascular resistance which is not affected by sympathetic blockade. The reduction in blood flow reduces the glomerular filtration rate and urine formation. The reduction in blood flow may be related to reduction in cardiac output during cross clamping and humoral mechanism related to increased renin concentration following cross clamping.

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Provided that cardiovascular function is optimised with maintenance of cardiac filling pressure, renal function is usually adequately maintained with production of 40-60ml/hr of urine. Some consider pharmacological support with mannitol. Mannitol acts in 2 ways. As an osmotic diuretic, it is a renal vasodilator and promotes renal tubular urine flow and second it is hydroxyl radical scavenger and lessens effects of ischaemia-reperfusion injury. To be most effective, mannitol must be administered before ischaemic episode. Renal Function in HIV Patients: HIV patients are more susceptible to acute tubular necrosis, glomerular nephritis, renovascular disease and HIV associated nephropathy which consists of proteinuria, azotemia, normal to large kidneys on ultrasonography. Hepatorenal syndrome (HRS): It is caused by functional renal vasoconstriction in response to splanchnic arterial vasodilatation. It occurs more commonly in patients with obstructive jaundice. The kidney is normal histologically and functions normally following a liver transplant or if transplanted into a recipient. Two types of HRS are recognized. Type 1 HRS is the more severe form and is characterized by an abrupt (within 2 weeks) decline of renal function, defined as a doubling of serum creatinine to greater than 2.5mg/dl or a 50% reduction in creatinine clearance to less than 20ml/min. Without liver transplantation, the mortality of this condition is greater than 90% at 3 months. Type II HRS is characterized by slowly progressing renal insufficiency (Serum creatinine greater than 1.5mg/dl and Creatinine clearance less than 40ml/min in a patient with refractory ascites. It has a much better prognosis. Type II may get converted to Type I with certain insults such as development of infections or use of NSAIDs. Recently diagnostic criteria of HRS is revised and creatinine clearance excluded.
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Diagnostic criteria for HRS: Cirrhosis with ascites Sr.creatinine greater than 1.5mg/dl Absence of another cause of renal failure Absence of ongoing fluid loss Absence of shock Absence of a sustained improvement in renal function following atleast 2 days of diuretic withdrawal and volume expansion with albumin. Recommended dose of albumin is 1gm/kg/day up to a maximum of 100gm/day. Cardiorenal Syndrome (CRS) Cardiorenal syndrome is disorder of the heart and kidneys in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. Renal insufficiency isfound in 20% to 40% of patients admitted to the hospital for heart failure. Features of CRS include the presence of renal insufficiency, tendency for hyperkalemia, low systolic blood pressure, diuretic resistance and anemia. The interdependence between the heart and kidneys makes it challenging to distinguish whether the heart or kidney is the main culprit in AKI. Five types of CRS are based on the initial onset of either heart or kidney dysfunction. Treatment modalities involve rapid volume removal with diuretics, hemodialysis and ultrafiltration. Intraabdominal hypertension and abdominal compartment syndrome: Intra-abdominal hypertension (IAH) is a graded phenomenon and can lead even to the end-stage abdominal compartment syndrome (ACS). A compartment syndrome exists when increased pressure in a closed anatomic space threatens the viability of enclosed tissue.
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IAH Sustained increase in intraabdominal pressure (IAP) equal to or above 12mmHg defines IAH. ACS Sustained IAP above 20mmHg with new-onset or progressive organ failure. IAH grading: Grade I Grade II Grade III Grade IV : IAP 12-15mmHg : IAP 16-20mmHg : IAP 21-25mmHg : IAP > 25mmHg

Risk factors for the development of IAH and ACS: - Related to diminished abdominal wall compliance - Related to increased intra-abdominal contents - Related to abdominal collections of fluid, air or blood - Related to capillary leak and fluid resuscitation Syndrome Abdominal compartment syndrome Potential Implication Multiple organ dysfunction Primary physiologic parameter Intra-abdominal pressure (IAP) Secondary parameter Abdominal perfusion pressure (APP) (APP = MAP IAP) Fluid Ascites Enclosure Abdominal cage Therapeutic intervention Lower IAP : ascites drainage Increase APP : Vasopressor, fluids Resuscitative plan - Open compartment
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Decompressive laparotomy Importance - Prevention of bacterial translocation and MODS can be life saving

Renal Function: An increasing number of large clinical studies have identified that IAH>15mmHg is independently associated with renal impairment and increased mortality. Reason may be multifactorial : reduced renal perfusion, reduced cardiac output, increased systemic vascular resistance and alterations in humoral and neurogenic factor. Elevated IAP significantly decreases arterial blood flow and renal venous return. Oliguria develops at an IAP of 15mm Hg and anuria at 30mm Hg in the presence of normovolemia and at lower levels in a patient with hypovolemia. Senior support If managing patients at risk of significant perioperative kidney injury, get support services from Nephrologist and Critical Care Physicians. Practical Approach to Perioperative Renal Protection: Preoperative: - Optimise volume status, cardiac output and systemic arterial pressure - Withhold nephrotoxic drugs - Maintain glycemic control in diabetic patients - Correct metabolic and electrolyte disturbances. - Delay surgery until recovery of acute renal dysfunction if possible - Arrange pre-operative dialysis for dialysis-dependent patients - Administer isotonic IV fluids and N-acetyl cysteine for prevention of radiocontrast-induced nephropathy. Intraoperative:
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- Optimise volume status, cardiac output and systemic arterial pressure. - Avoid nephrotoxic drugs - Maintain tight glycemic control in all patients - Urinary catheter aiming for a urine output >0.5ml/kg/hr. - Monitoring of CVP and cardiac output - Vasopressors if indicated - Monitoring of anaesthetic and surgically induced hemodynamic alterations. Cardiac Surgery: - Maintain adequate flow and MAP during CPB - Limit the duration of CPB - Avoid excessive hemodilution - Avoid red cell transfusion - Consider extra corporeal leucodepletion - Consider hemofiltration during CPB - Consider off-pump coronary artery bypass surgery.

Vascular Surgery: - Consider abdominal aortic endovascular aneurysm repair Postoperative: - Avoid nephrotoxic drugs - Maintain strict glycemic control - Promptly treat acute cardiac dysfunction - Control haemorrhage - Manage sepsis aggressively - Recognise and treat rhabdomyolysis - Recognize and treat inta-abdominal hypertension
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- Provide appropriate organ support of MODS - Institute renal replacement therapy if necessary after consulting with Nephrologist and Critical care physician.

Anaesthetic Considerations: With the exception of ketamine, all commonly used anaesthetic agents decrease systemic vascular resistance, reduce both contractility and cardiac output and attenuate the normal response to hypovolemia. Hemodynamically unstable patient is at risk of cardiovascular collapse. In the preoperative period, get adequate IV access, correct and restore intravascular volume deficits and if necessary insert arterial line, CVP and other invasive monitors. Induction Agents: Adjust dose of induction agents. Many patients at risk of AKI will need a reduced dose. Prior to renal excretion, induction agents undergo redistribution and biotransformation into inactive products. In hypovolemia there is diversion of blood to essential organs and effects of induction agents may be exacerbated. Volatile agents such as isoflurane and seroflurane contain nephrotoxic fluoride, which poses only a theoretical risk and there is little evidence for avoidance of these agents. Opioids: AKI prolongs the action of opioids as they are renally excreted. Administer lower doses of these agents. Muscle relaxants: Suxamethonium should be avoided in AKI patients with documented raised potassium levels as it increases potassium efflux from muscle cells. Nondepolarising muscle relaxant have an altered duration of action, especially in acidosis. Avoid pancuronium and Vecuronium as they may remain unchanged in urine.
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Epidural Anaesthesia: Use it judiciously in the intraoperative and postoperative period as sympathetic blockade can induce or worsen hypotension. Effect of PEEP: PEEP causes a decrease in urine output, sodium excretion and creatinine clearance. Reasons are multifactorial including a decrease in cardiac output, renal blood flow, intravascular volume and reflex sympathetic nerve activation and altered release of various hormones including catecholamines, renin-angiotensinaldosterone, antidiuretic hormone contribute to the effects on renal function. Patient volume status and the amount of PEEP both contribute to alterations in renal function. Conclusion: Acute kidney injury is a life threatening clinical problem and it is common perioperatively. Very often it is poorly recognized and managed and caries very high morbidity and mortality and increases health care cost. An apparently successful surgical outcome may not mean a successful renal outcome. With good initial assessment and simple measures including fluid management and avoidance of nephrotoxic drugs, it is preventable. Patients with AKI are often complex to treat, and senior help should be sought at an early stage. Those who recover may have a lasting deterioration in renal function or distant organ damage and are more likely to have complications in the future.

Patients who develop AKI and have complications such as hyperkalemia, acidosis or volume overload may require renal replacement therapy. No magic pharmacologic agent to protect kidney from a variety of insults. In order to get optimal patient management, early involvement of Nephrologist and Critical care physician will be helpful.
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References: 1. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Volume 2/ Issue 1 / March 2012. Kidney International Supplements. 2. Emma Borthwick, Andrew Fergusin. Perioperative Acute Kidney Injury : risk factors, recognition, management and outcomes. BMJ/ 10 July 2010, Volume 341. 3. DrCharlotte Battle,Dr Alistair Hellewell, Royal Devan & Exeter Hospital. Perioperative Renal Dysfunction. Anaesthesia Tutorial of The Week 227 (13th June, 2011). 4. Stephen T Webb, J Stephen D Allen. Perioperative renal Protection. BJA, CEACCP, volume8issue 5 pp.176-180; Aug.2008. 5. Yao and Artusios Anaesthesiology. Problem Oriented Patient Management. 7th Edition, Editor-in-Chief, Fun-Sun F.Yao. 6. Avoiding Common Anaesthesia Errors. Eds.Catherine Marcucci, Norman A, Cohen, David G. Metro, Jeffrey R.Kirsch;2008 Lippincott Williams & Wilkins. 7. Manual of Nephrology, Seventh Edition, Robert W.Schrier, MD, 2009 by Lippincott Williams & Wilkins. 8. Nephrology Subspeciality Consult. Second Edition, David Windus. The Washington Manual, Subspeciality Consult Series. 9. Evidence Based Practice of Anaesthesiology, Lee A Fleischer. 10.Bobbie Jean Sweitzer. Preoperative Assessment and Management, Second Edition, 2008; Lippincott Williams and Wilkins.

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