|Year : 2009 | Volume
| Issue : 4 | Page : 553-559
|Renal replacement therapy in sepsis-induced acute renal failure
Senaka Rajapakse1, Chaturaka Rodrigo1, Anoja Rajapakse2, Dinoo Kirthinanda1, Sujani Wijeratne1
1 Faculty of Medicine, University of Colombo, Sri Lanka
2 Newark Hospital, Sherwood Forest NHS Trust, Newark, United Kingdom
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|Date of Web Publication||8-Jul-2009|
| Abstract|| |
Acute renal failure (ARF) is a common complication of sepsis and carries a high mortality. Renal replacement therapy (RRT) during the acute stage is the mainstay of therapy. Various modalities of RRT are available. Continuous RRT using convective methods are preferred in sepsis-induced ARF, especially in hemodynamically unstable patients, although clear evidence of benefit over intermittent hemodialysis is still not available. Peritoneal dialysis is clearly inferior, and is not recommended. Early initiation of RRT is probably advantageous, although the optimal timing of dialysis is yet unknown. Higher doses of RRT are more likely to be beneficial. Use of biocompatible membranes and bicarbonate buffer in the dialysate are preferred. Anticoagulation during dialysis must be carefully adjusted and monitored.
Keywords: Acute renal failure, Sepsis, Renal replacement therapy, Dialysis, Hemofiltration
|How to cite this article:|
Rajapakse S, Rodrigo C, Rajapakse A, Kirthinanda D, Wijeratne S. Renal replacement therapy in sepsis-induced acute renal failure. Saudi J Kidney Dis Transpl 2009;20:553-9
|How to cite this URL:|
Rajapakse S, Rodrigo C, Rajapakse A, Kirthinanda D, Wijeratne S. Renal replacement therapy in sepsis-induced acute renal failure. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Mar 18];20:553-9. Available from: http://www.sjkdt.org/text.asp?2009/20/4/553/53241
| Introduction|| |
Deterioration of renal function over days to weeks is termed acute renal failure (ARF) and affects around 35% of patients in intensive care units.  Sepsis is the cause in about 50% of cases of critically ill patients with ARF. The overall mortality rate of ARF is about 45%; however, the mortality rate of sepsis-induced ARF is more than 70%. Despite advances in management strategies, in particular renal replacement therapy (RRT), the outcome of ARF in patients with sepsis remains poor.
The treatment of ARF includes the management of life threatening emergencies such as hyperkalemia, acidosis, and pulmonary edema, correcting causes of ARF where possible such as treatment of underlying sepsis, prevention of renal injury by contrast media and nephrotoxic drugs, adequate nutrition and other supportive measures. Renal replacement therapy, until renal function recovers, remains the definitive mainstay of treatment. In this paper, an attempt is made to review the role of RRT in patients with ARF.
| Modalities of Renal Replacement Therapy|| |
Although many different modalities of RRT are available, they all rely on two basic principles, diffusion and convection.  Dialysis depends primarily on diffusion, while hemofiltration uses convection. The two modalities may be combined.
Peritoneal dialysis, where the peritoneum acts as the semi-permeable membrane, is rarely used in critically ill patients now. A peritoneal catheter is introduced through the anterior abdominal wall into the peritoneal cavity and dialysis solution containing sodium, calcium, magnesium and lactate (the buffer) is cyclically introduced into, and drained out from the peritoneal cavity. While urea, creatinine and other undesired molecules diffuse down their concentration gradients, the solutes in the dialysate will readjust the constituents of plasma. As these patients are generally fluid overloaded, glucose in concentrations of 1.25 to 4.25% is added to the dialysate to create ultrafiltration of water.
Intermittent hemodialysis (HD) is used in hemodynamically stable patients with ARF. Heparinized blood from the patient is made to pass through an extracorporeal system of tubing at a rate of 300 to 500 mL and is separated in the dialyzer by a semi-permeable membrane from a crystalloid solution (dialysis fluid) flowing at a rate of 500 to 800 mL. The concentration of molecules in the dialysis fluid is such that it draws out molecules that are present in excess in blood along a concentration gradient. The degree of diffusion is also dependent on relative sizes of molecules. Urea, creatinine and other toxins pass down their chemical gradients into the dialysis solution while the reverse process restores the natural composition of plasma. When removal of water is required, a process called ultrafiltration is used. By adjusting the pressure difference on either side of the membrane, an osmotic drag can be created for water molecules to pass down into the dialysate, resulting in a net loss of water. While sodium, calcium and magnesium are replaced by dialysis fluid, bicarbonate is replaced as lactate on the assumption that lactate will be converted into bicarbonate inside the body. The major disadvantage of dialysis is that although it removes smaller mole cules such as urea efficiently, clearance of middle size (creatinine) and larger molecules can be quite unsatisfactory. 
Convective methods are preferred to conventional dialysis in critically ill patients.  , Hemofiltration is the most commonly used modality. Blood is passed through an extracorporeal system and a pressure is created on that side of the membrane to filter out most of the smaller and middle size molecules (up to 20,000 Da). The clearance of urea, creatinine and phosphate are all similar. The resultant ultrafiltrate is discarded and replaced with replacement fluid containing desirable concentrations of solutes. If adjustments are needed for fluid overload, the amount of fluid replaced is reduced so that it is lesser than the amount removed. Two methods of hemofiltration are used, namely continuous arteriovenous hemofiltration (CAVH) and continuous venovenous hemofiltration (CVVH).
In CAVH, the femoral artery is cannulated and blood is sent through an extracorporeal circuit. The arterial pressure drives the ultrafiltrate through the membrane. Though the design is simple, the method has the risk of a simple breach in the closed circuit resulting in exsanguination. Furthermore, the ultrafiltration rates achieved by arterial pressure alone are not adequate to clear solutes adequately as demanded in a patient with ARF (10 to 15 mL/min in normotensive patients), and clearance rates are even lower in hypotensive patients. Slow blood flow can result in frequent clotting of the extracorporeal circuit.
In CVVH, a vein (usually the femoral or internal jugular vein) is accessed instead of an artery. The subclavian vein is avoided because of the risk of frequent clotting and limb edema. The venous blood is passed through an occlusive pump with safety features to detect air bubbles. The functioning of the pump gives better control over filtration and rates over 100 mL/min can be achieved. CVVH is currently the preferred modality of RRT in critically ill patients.
Both arteriovenous and venovenous hemofiltration methods can be combined with dialysis if the clearance rates are not adequate. In such a setting, a small fraction of the plasma undergoes filtration and the remaining is sent through a dialyzer making sure even small quantities of undesirable molecules are removed from the system. However, it is thought that clearance rates with venovenous filtration are often adequate, and that additional dialysis is rarely necessary.
| The use of Renal Replacement Therapy in Acute Renal Failure|| |
The key issues in the use of RRT in sepsisinduced ARF are:
The modality of RRT
- The preferred modality of RRT (IHD, CAVH, CVVH, Peritoneal dialysis)
- Optimal time of initiation of RRT
- Optimum dialysis dose
- Type of membrane
- Type of dialysate
Continuous renal replacement therapy (CRRT) has an advantage over intermittent HD in that it provides greater hemodynamic stability, easier fluid removal and greater flexibility in providing parenteral nutrition as a result of greater control over fluid balance. The disadvantages of continuous therapy are the need for long-term anti-coagulation to the patient to maximize the life span of the filter, and complications related to vascular access. Furthermore, continuous therapy is at least 2.5 times more expensive than regular intermittent dialysis.
Current evidence however, does not demonstrate a significant advantage of CRRT over IHD in terms of mortality or renal recovery. A recent meta-analysis by Bagshaw et al  compared CRRT with IHD as the initial modality of RRT and concluded that there was no significant difference in outcome, in terms of mortality or renal recovery between the two modalities. There was a suggestion that CRRT had fewer episodes of hemodynamic imbalance and better fluid balance. However, the relevant studies had numerous flaws with regard to design, data description, conduct and quality. A systematic review by Pannu et al  also showed that clinical out comes with CRRT and IHD were comparable. Overall, the current state of evidence does not indicate a clear advantage of the use of CRRT over IHD in sepsis-induced ARF, although the evidence base is not strong enough to make a clear recommendation. Given its advantages in patients who are hemodynamically unstable, CRRT is likely to be the more favored modality, where available. In hemodynamically stable patients, there is inadequate justification as yet, to favor one modality over the other. However, particularly in resource limited settings, IHD remains the main modality of RRT. Peritoneal dialysis has been shown to be less effective,  as well as more costly and requires greater manpower resources and is not a recommended modality of dialysis in sepsis-induced ARF.
Whether dialysis or hemofiltration will help in removal of inflammatory mediators and hence help alleviate the cytokine storm in severe sepsis is not known. Conventional ultrafiltration rates are probably inadequate to have a significant effect on cytokine removal and for this purpose, high volume hemofiltration (HVHF), using ultrafiltration rates > 35 mL/kg/hour have been used. There is some evidence of improved hemodynamics with reduced need for vasopressor support ,, and a trend towards improved survival with HVHF,  but further studies are required. It has been suggested that the improved hemodynamics seen with CRRT may be a result of cytokine removal, in addition to mild hypothermia, resulting in increased systemic vascular tone.
Timing of dialysis
The specific indications for initiation of RRT in sepsis-induced ARF are controversial; the traditional indications used in chronic renal failure such as encephalopathy, pericarditis and coagulopathy are less common in ARF, and these manifestations may be due to numerous other reasons in critical illness. Incipient or established fluid overload and electrolyte imbalance and/or acidosis, which do not respond adequately to conservative management, are clear indications for initiation of RRT. Evidence regarding the ideal timing of dialysis is scarce. Three different studies ,, have shown inconclusive results. A prospective cohort study  showed that the risk of death was lower when dialysis was started at lower blood urea levels. A specific blood urea nitrogen or creatinine level at which RRT should be commenced in ARF is difficult to define, and no firm recommendation can be made based on current evidence. Direct clinical or biochemical indications will guide the initiation of RRT in sepsis-induced ARF. However, given the limited evidence of possible benefit of early initiation of RRT, it would seem logical to initiate RRT early rather than late, especially in rapidly developing, symptomatic, oliguric renal failure with metabolic derangement.
The adequacy of RRT
The use of urea clearance alone as a measure of adequacy of dialysis has been questioned in recent times, as many other small and middle sized molecules contribute to the morbidity. The measurement of Kt/V is the standard method of assessing adequacy of dialysis, where K is the urea clearance of the dialysis membrane used (mL/min), t is the duration of dialysis (min), and V is the volume of distribution of urea in the patient (mL). A Kt/V value of greater than 1.2 has been traditionally accepted as a measure of adequate dialysis. The adequacy of dialysis and corresponding Kt/V values have been extensively studied in patients with chronic renal failure. (The National Cooperative Dialysis Study, Dialysis Outcomes Quality Initiative). However, the high catabolic rate in sepsis-induced ARF, variable fluid volumes, and the post-dialysis "rebound" of urea concentrations from hypoperfused organs, limits the use of Kt/V as a measure of adequacy of dialysis in critically ill patients. The "dose" of IHD required in ARF is often described using the hours of dialysis, rate of blood flow, and frequency of dialysis. Since urea equilibrates rapidly across the dialysis membrane, urea clearance in CRRT is essentially equivalent to the volume of effluent dialysate (including any ultrafiltered fluid), and therefore CRRT dose is commonly expressed as liters/kg/ hour of effluent.
Intermittent HD: In 1986 Gillum et al  prospectively studied the effect of dialysis intensity on survival in patients with ARF. The trial had two groups of patients; the first group which received intensive intermittent dialysis (daily dialysis with 5 to 6 hours per treatment) and the other group, which received standard non intensive prescription of 5-hour treatments either on a daily basis, or every third day basis. The survival in the two groups did not vary significantly. The technical capacities of modern dialyzers have increased significantly since then, and these findings have been challenged in recent studies. Schiffl et al  in another trial demonstrated a higher survival among patients with ARF treated with daily IHD compared with those treated with thrice-weekly IHD. However, the dose of dialysis in the conventional group was lower than that recommended in chronic renal failure. One of the exclusion criteria was the need for CRRT, which meant that the patients included were not acutely ill, and may not be representative of the true picture of ARF. The overall mortality of the study was 37%, which is much lower than mortality figures in other studies, which further strengthens the previous argument.
Continuous RRT: Ronco et al  evaluated the dose effect on outcome of patients treated with CVVH. They randomized patients to three groups and prescribed three ultrafiltration rates based on body weights for each group; 20, 35, 45 mL/ hr/kg. There was only a 3 to 6% variation of prescribed therapy and therapy actually given to patients. A significant survival benefit was seen in patients who received middle and high ultrafiltration rates versus the low filtration rate group. There was no difference between the middle and high filtration rate groups. Thus, it appears that a minimum ultrafiltration rate of 35 mL/kg/hour is required to have a survival benefit. It was also noted that, in the middle flow rate group, survival of patients with sepsis was significantly lower compared to non-sepsis induced ARF, although a similar difference was not observed in the high flow rate group suggesting that there may be a "sepsis dose" for ultrafiltration. A significant finding of the study was the inadequacy of routine CVVH prescriptions and ultrafiltration rates used in most centers.
For successful hemofiltration, the filtration fraction (ultrafiltration rate/blood flow rate) has to be around 30 to 35%, and to achieve an ultrafiltration rate of 35 mL/kg/hour, at least 250 mL/min of blood flow is necessary as opposed to the current rate of about 150 mL/min used in most centers.
Evidence regarding the ideal dose of RRT in sepsis-induced ARF is inadequate to make firm recommendations,  , and more studies on larger cohorts of patients are required. It seems reasonable to assume, however, that higher doses of RRT are desirable, and in the case of CRRT, an ultrafiltration rate of 35 mL/kg/hour is more likely to improve survival.
Type of membrane
The semi-permeable membrane that is present in the dialyzer has a significant influence on the efficiency of the procedure. While many types of membranes are used, they can be categorized as biocompatible membranes and others. Biocompatibility is a measure of the degree of activation of neutrophils, mast cells, monocytes, platelets and complement systems of blood when exposed to the membrane. Activation of these components can result in the release of inflammatory mediators such as leukotriens, histamines, thromboxanes, prostaglandins, TNFalpha and beta microglobulins. The activation of these mediators can result in bronchoconstriction, vasoconstriction and hypotension adding further to the burden of illness in sepsis. The earlier cellulose-based dialysis membranes were bio-incompatible, but modification of the cellulose component has made it possible to create synthetic polymers that are biocompatible (e.g. acetate-substituted cellulose and non-cellulosebased polyacrylonitrile, polysulfone, and polymethylmethacrylate).
Synthetic membranes used nowadays have the added benefit of adsorbing mediators involved in the systemic inflammatory response syndrome. Evidence from several studies ,,, suggests that the use of membranes made of unsubstituted cellulose is associated with an increased risk of death, hence, their use is not recommended in patients with ARF. Synthetic membranes are more expensive, and differ in their efficiency of solute clearance, although there is no clear evidence favoring a particular type of synthetic membrane as yet.
Membranes are also characterized in terms of flux (i.e. permeability to water and larger solutes). High-flux membranes are preferred in CRRT because increased permeability to water facilitates hemofiltration. However, there is no demonstrated significant difference in terms of outcome between high-flux and low-flux membranes. ,,
Type of dialysate
In the case of IHD, dialysate is produced as needed by the dialysis machine by mixing water with electrolytes. Replacement solution for CRRT must, on the other hand, be sterile, and is either purchased or produced locally. Metabolic acidosis is corrected by the use of a buffer such as acetate, lactate or bicarbonate. Bicarbonate is preferred in CRRT in critically ill patients, because of concerns that in multi-organ failure, lactate and acetate may not be adequately converted to bicarbonate. Barenbrock et al  compared the use of bicarbonate with lactate in patients receiving CRRT. While there was no significant reduction in mortality, the use of bicarbonate buffer significantly reduced the risk of cardiovascular events. According to one small study, bicarbonate is not superior to acetate in IHD.  Additionally, no difference was found between acetate and lactate buffers. 
Anticoagulation is required in both IHD and CRRT to prevent clotting of the filter in the extracorporeal circuit, this is of particular importance in CRRT. Because of the coagulopathy, which frequently occurs in severe sepsis, anti-coagulation can result in serious bleeding. Unfractionated heparin is most commonly used, although the optimal degree of anticoagulation is not known. Fractionated heparin is not used because of the difficulties in reversing its effects. In patients at high-risk of bleeding, saline flushes or citrate infusions are used. There is some evidence that citrate reduces the risk of bleeding compared to heparin,  although it can cause hypocalcemia, metabolic alkalosis and citrate toxicity. Hirudin maybe an alternative to heparin, but data is inadequate at present.
| Conclusions|| |
Despite advances in medical science and technology, the mortality rate of ARF continues to be between 50 to 80%. While clear evidence of out-come benefit is still lacking, CRRT may be the preferred mode of renal replacement in sepsis-induced ARF, especially in hemodynamically unstable patients. It is recommended that RRT is commenced early in the setting of ARF, as complications such as metabolic acidosis will compromise hemodynamic stability and further compromise renal perfusion and function. Higher doses of dialysis are more likely to be beneficial, though the optimal dose is yet unknown. Non-cellulose membranes are best avoided, and bicarbonate is the preferred buffer solution. Careful anticoagulation must be aimed at preventing clotting of the filter, and avoiding serious hemorrhage. Renal replacement in sepsisinduced ARF is expensive and labor intensive, but remains one of the key life saving interventions in the management of severe sepsis. The results of the ATN and RENAL trials will hopefully resolve some of the controversies that exist at present.
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Consultant Physician and Senior Lecturer in Medicine, Faculty of Medicine, University of Colombo
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