Editorial Review. Andrew Davenport 1, Evangelos Cholongitas 2, Elias Xirouchakis 2 and Andrew Kenneth Burroughs 2. Introduction

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1 Nephrol Dial Transplant (2011) 22: doi: /ndt/gfr354 Advance Access publication 20 June 2011 Editorial Review Pitfalls in assessing renal function in patients with cirrhosis potential inequity for access to treatment of hepatorenal failure and liver transplantation Andrew Davenport 1, Evangelos Cholongitas 2, Elias Xirouchakis 2 and Andrew Kenneth Burroughs 2 1 UCL Centre for Nephrology, The Royal Free Hospital, University College London Medical School, London, UK and 2 The Royal Free Sheila Sherlock Liver Centre, The Royal Free Hospital, University College London Medical School, London, UK Correspondence and offprint requests to: Andrew Davenport; andrewdavenport@nhs.net Abstract Serum creatinine is universally used to assess renal function in clinical practice. Creatinine and changes in serum creatinine are used to define acute kidney injury and hepatorenal syndrome (HRS) in patients with progressive liver disease. In addition, creatinine is a key variable in the calculation used to determine priority for liver transplantation in many countries. As there is no universal standardized creatinine assay, there is variation in creatinine determinations between laboratory assays, compounded by assay interference due to chromogens, including bilirubin. This leads to patients with the same actual renal function potentially being offered different treatment options, in terms of access to therapy for HRS and priority waiting time for liver transplantation. Alternative methods for assessing renal function either also tend to overestimate renal function or are too time consuming and expensive to provide practical alternatives for standard clinical practice. Standardization of creatinine assays with readily available reference standards would help minimize interlaboratory variation; of the current creatinine assays, enzymatic creatinine appears more accurate, but even this is inaccurate at high bilirubin concentrations. Further work is required to determine whether interpatient variation can be reduced by correcting creatinine and cystatin measurements for muscle mass. Keywords: chronic liver disease; cirrhosis; cystatin C; GFR; renal function creatinine Introduction An acute deterioration in renal function in patients with chronic liver disease and also following liver transplantation is strongly associated with increased mortality [1 3]. Acute kidney injury (AKI) is now defined in terms of an absolute or percentage increase in baseline serum creatinine [4], and the hepatorenal syndrome (HRS) uses creatinine both as a major inclusion criteria (>1.5 mg/dl or 133 lmol/l) (Table 1) and also to subclassify patients into HRS Type 1, with a doubling of the serum creatinine to >2.5 mg/dl (222 lmol/l) within 2 weeks, and Type 2, with slower deterioration in renal function [5]. Although the mortality of patients with cirrhosis and HRS Type 1 remains high, newer treatments combining the vasopressin analogue terlipressin with daily albumin infusion have improved outcome [6]. In addition, the traditional Child- Turcotte-Pugh (CTP) staging of chronic liver disease which did not include renal function and has now been replaced by the model for end-stage liver disease [MELD score ¼ log e (creatinine mg/dl) log e (bilirubin mg/ dl) log e (INR) 1 6.4] [7], to predict short-term mortality for patients with cirrhosis awaiting liver transplantation, and is now used by the United Network of Organ Sharing (UNOS), Eurotransplant and several other Asian and South American countries to allocate liver transplants. However, the introduction of organ allocation based on MELD scores has led to a relative increase in the number of men receiving liver transplants compared to women (Figure 1). It has been suggested that this apparent change in organ allocation may be due to differences in serum creatinine measurements between the sexes [8] and that the creatinine may weigh too heavily within the MELD score [9]. For example, a cirrhotic patient with a normalized international ratio of 1.2 and serum bilirubin of 161 lmol/l (9.4 mg/dl) would have a MELD score of 20 with a serum creatinine of 100 lmol/l (1.13 mg/dl), 24 with a creatinine of 150 lmol/l (1.69 mg/dl) and 26 with a creatinine of 200 lmol/l (2.26 mg/dl). Moreover, the assumption that mortality is constant for patients with creatinine values >1 mg/dl (88 lmol/l) or >4 mg/dl (354 lmol/l) is likely to be false, and as such, a modified MELD score including log e [1 1 creatinine (mg/ dl)] without boundaries and a lower weight for creatinine has been proposed for centres outside the USA [10, 11]. In addition, terlipressin, which has recently been introduced to treat patients with HRS, is expensive and is therefore often restricted to patients fulfilling the HRS serum creatinine criteria, although potentially terlipressin may be more effective in reversing renal dysfunction when used earlier ÓÓThe Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oup.com

2 2736 Nephrol Dial Transplant (2011): Editorial Review Table 1. Criteria for diagnosis of hepatorenal failure in patients with established hepatic cirrhosis, adapted from reference [5] 1. Cirrhosis with ascites 2. Serum creatinine >1.5 mg/dl (133 lmol/l) 3. Absence of shock 4. Absence of hypovolaemia as defined by no sustained improvement of renal function (creatinine decreasing to <1.5 mg/dl or 133 lmol/l) following at least 2 days of diuretic withdrawal (if prescribed diuretics) and volume expansion with albumin at 1 g/kg (up to a maximum of 100 g/day) 5. No current or recent treatment with nephrotoxic drugs 6. Absence of parenchymal renal disease as defined by proteinuria <500 mg/day, no microhaematuria (<50 RBC per high power field) and normal renal ultrasonography Fig. 1. Percentage of female patients receiving liver transplants prior to and following the introduction of the MELD scoring system to allocate liver transplants by UNOS and Eurotransplant. [12], when response to volume filling is inadequate irrespective of the serum creatinine concentration [13]. Thus, renal function as assessed by serum creatinine estimation has a major impact on treatment options for patients with chronic liver disease. However, creatinine is only an indirect marker of renal function, i.e. of glomerular filtration rate (GFR). Creatinine derives from the non-enzymatic conversion of creatine which is synthesized in the liver and stored in muscle. Creatine synthesis is reduced in cirrhosis [14] and combined with muscle wasting and reduced protein intake, serum creatinine-based methods overestimate renal function. Another problem, not often recognized by clinicians, is that there is no international standard for the laboratory measurement of serum creatinine [15]. Assessment of GFR based on creatinine Serum creatinine determination. Serum creatinine is a routine laboratory test and widely accepted for the assessment of renal function in the general population. However, serum creatinine is also dependent upon other factors, including dietary meat ingestion, particularly stewed meat, the rate of creatine conversion to creatinine, renal tubular secretion of creatinine, urinary flow rate, hydration status as well as the total pool of body creatine (total muscle mass) [16]. Muscle mass and muscle turnover are important extrarenal factors leading to differences in serum creatinine measurements between individuals with the same renal function (same GFR), but of different ages, sex, races, body mass index or having concomitant chronic catabolic disease (e.g. malignancy or cirrhosis) [16]. Thus, women typically have lower creatinine values compared to men with the same renal function [8] and the elderly may have overestimation of their renal residual function compared to younger individuals. Differences in muscle mass and diet typically account for the higher GFR in Afro-Caribbean patients compared to South Asians with the same serum creatinine [17]. Patients with cirrhosis typically have decreased creatine production, due to liver dysfunction, protein-calorie wasting with muscle wasting and the oedematous state of decompensated cirrhosis leading to an increased creatinine distribution volume. In addition, serum creatinine can also be affected by diuretic therapy and also cephalosporins and calcitriol, which affect tubular secretion of creatinine [18]. Not surprisingly, meta-analysis reported that a serum creatinine within the normal reference range does not exclude a significant impairment in GFR [19]. An additional problem is that creatinine assays are subject to interference by chromogens, bilirubin (both conjugated and unconjugated), typically reducing the measurement (Table 2). Most laboratories employ a modified colourimetric Jaffe reaction, which is simple and relatively inexpensive. Several modifications have been developed to reduce interference with the Jaffe reaction (including the kinetic alkaline picrate, end-point, rate-blanked and compensated methods) and also the introduction of enzymatic methods (using creatininases and creatininase hydrolases). Enzymatic methodshavebeenreportedtobemoreaccuratethanjaffebased assays, but are generally more expensive [20]. In addition, there is no universal reference standard for creatinine which is readily available for laboratories to standardize their assay. In the UK, National Health Service laboratories were sent isotope dilution mass spectroscopy (IDMS) standards to develop their correction factors for their own assay. However, IDMS standards do not allow for interfering chromogens, and as such, there were marked differences in creatinine determination between UK laboratories for patients with chronic liver disease placed on liver transplant waiting lists [21]. Even in general hospital practice, interlaboratory coefficients of variation have been reported to vary between 4.37 and 8.74%, despite using creatinine assays corrected by IDMS standards [22]. Enzymatic creatinine is currently a more accurate assay [20, 23] but even so enzymatic assays become progressively inaccurate with serum bilirubin concentrations >19.9 mg/dl (340 lmol/l), which is somewhat better than the 9.9 mg/dl (170 lmol/l) cut-off for kinetic Jaffe assays. Although in cases of marked hyperbilirubinaemia, sample dilution followed by enzymatic creatinine measurement improves diagnostic accuracy. For modified Jaffe-based assays even with an identical method, the effects of bilirubin will depend on the software of the biochemical analyser, for example, rate blanking will reduce the analytical error caused by bilirubin.

3 Nephrol Dial Transplant (2011): Editorial Review 2737 Table 2. Potential interfere with colourimetric determination of plasma creatinine a Creatinine increased Glucose IgM gammopathy Ketones Ketoacids Uric acid Haemolysed haemoglobin F >600 mg/dl Ascorbic acid Cephalosporins Dopamine 2-Phenyl-1,3-indadion Creatinine decreased Bilirubin a Interference differs with assays, being greatest for unmodified and less with modified assays (including kinetic alkaline picrate, end point, rateblanked and compensated methods) and enzymatic creatinine. Even so, results from assays using the same modification may well differ depending upon the individual biochemical analyser used. However, methods using a heating coil that allows measurements at 41 C greatly reduces bilirubin error. Thus, the interference effect of hyperbilirubinaemia depends not only upon assay modifications but also varies between manufacturers and the assay platform. Implications of Cr inaccuracy on prognosis and liver allocation of patients with cirrhosis. MELD scoring is used for organ allocation based on a sickest first policy and the prediction of short-term prognosis in patients with cirrhosis. The MELD score is considered better than CTP in part due to the inclusion of creatinine as a prognostic factor and also by replacing the prothrombin time by the normalized international ratio, to try and standardize measurements and reduce interlaboratory variation in results [23]. Modification of the CTP score by including creatinine has been reported to improve predictive performance compared to the standard CTP score but has not been generally adopted in clinical practice [24]. As serum creatinine tends to overestimate GFR in cirrhotics, the question arises as to whether this has clinical consequences. A recent study showed that measured GFR estimated using 125 I-iothalamate was superior to serum creatinine in assessing the mortality risk on the liver transplant waiting list, with a linear rise in the risk of death as the GFR decreased from 60 to 20 ml/min/1.73 m 2 [25]. In addition, the substitution of creatinine with 125 I-iothalamate measured GFR value led to a small but significant improvement of the discriminative ability of MELD score (c-statistic for MELD-GFR: versus for standard MELD, P < 0.001) [23]. As women typically have lower serum creatinine values compared to men, analysis of the UNOS database showed that although women were listed with lower median MELD scores compared to men (14 versus 15, P < 0.001), they were more likely to die while waiting for a liver transplant in the post-meld era compared to pre-meld [26]. These findings cannot be explained simply by the difficulty of finding a suitably sized graft for women due to their smaller size [27] but can be explained by considering that similar serum creatinine values represent a worse GFR in women. Correcting the serum creatinine in females for the same GFR as in males increased the MELD score by 2 or 3 points in 65% of female liver transplant candidates [8]. Although a score corrected for female candidates (MELD gender) has been suggested [10], this has not been adopted into clinical practice, so whether it would improve organ allocation for women is unknown. Differences in creatinine and GFR are not just limited to sex, as serum creatinine is typically lower in vegetarian patients from the South Asian subcontinent compared to Northern European Caucasoids and greatest in Afro-Caribbeans and thus racial disparities are also an issue for organ allocation. As serum creatinine is the major criteria for HRS, access to treatment with terlipressin and albumin is not only more likely in male Afro-Caribbeans than female South Asians but also by starting at a higher GFR there may well be potentially greater response [12, 13]. Interference with creatinine measurement is more likely with bilirubin concentrations >3.68 mg/dl (63 lmol/l), particularly when using unmodified Jaffe assays [23], resulting in significant differences in creatinine values, and, up to a 7-point variation in the MELD score, particularly compared to patients with serum bilirubin values >23.4 mg/dl (400 lmol/l) [28]. The Jaffe unmodified colourimetric method showed the greatest interference with bilirubin and modified-delayed Jaffe-compensated assays the least interference. Nevertheless, all four methods, which were evaluated in one study, including an enzymatic method, had poor or very poor agreement, resulting in significant differences in MELD scores [28]. Interestingly, in another study, there was significant variation in creatinine values and MELD scores from four UK liver transplant centres, which had calibrated their assays using IDMS traceable standards and even between those using the same laboratory method [21]. Similar results were also reported from seven European centres, giving a difference of up to 3 MELD points in the same patient between assays [29]. Renal clearance of creatinine. Creatinine clearance is not an accurate method for renal function assessment as it has been shown to overestimate measured GFR in numerous studies using inulin clearance. The limitations of creatinine clearance are associated not only with the use of serum creatinine in the mathematical equation [(Urine Cr 3V urine )/Serum Cr ] but also with the influence of several factors which increase tubular creatinine secretion [30], including proteinuria, diet (a heavy meat meal can increase 24-h creatinine clearance by 37%) and extrarenal elimination of creatinine by microorganisms. In addition, there may be up to 25% variation in GFR estimation based on creatinine clearance, due to incomplete urine collection, errors in urine volume measurements, variations in tubular excretion or reabsorption of creatinine and other unpredictable factors [16]. Particularly in cirrhosis, creatinine clearance has shown that it overestimates the true GFR [24], possibly related to the increased proportion of creatinine secreted by the tubule compared to creatinine filtered by the glomerulus during cirrhosis [31]. Thus, there is no evidence that creatinine clearance is superior to serum creatinine in determining renal function in cirrhotics. Mathematical formulae based on serum creatinine. A number of different equations have been derived to incorporate serum creatinine to provide an estimation of GFR

4 2738 Nephrol Dial Transplant (2011): Editorial Review (egfr). These include the Cockcroft Gault and Modification of Diet in Renal Disease (MDRD) formulae [32, 33]. The Cockcroft Gault formula requires serum creatinine, weight, gender and age, whereas the MDRD incorporates serum creatinine, ethnicity, gender and age (MDRD-4) or creatinine, ethnicity, gender, age, albumin and urea (MDRD- 6) [16, 33]. However, it must be recognized that the MDRD equation was derived from a population of healthy stable patients with chronic kidney disease, a substantially different population to those with acute or chronic liver disease. In cirrhosis, although there is discrepancy when compared to 125 I-iothalamate [34], MDRD-6 is considered to be a more robust formula compared to C-G, possibly because it incorporates urea and albumin, which are abnormal in cirrhotics [35] and excludes body weight, a variable which may be difficult to assess in malnourished patients with ascites. However, the MDRD-4 formula is typically used to calculate egfr, as in population screening is not inferior to the original six-variable formula [36]. In cirrhosis, both C-G and MDRD formulae typically overestimate isotopic GFR, particularly in those patients <50 years or with ascites [37]. In addition, the MDRD formulae have been reported to overestimate GFR for isotopically measured GFR values of <40 ml/min prior to liver transplantation and then underestimate the GFR for isotopically measured GFR values >40 ml/min post-liver transplantation [34]. The MDRD equation was based on a population with stable chronic kidney disease and the errors in estimating GFR increased with higher GFR, such that for a reported egfr of 50 ml/min/1.73m 2 describes a range of GFRs between 35 and 65 ml/min/1.73m 2. As such, some laboratories simply report higher egfr values as >60 ml/min, due to the inaccuracy in estimating higher values. To try and overcome these inaccuracies, a newer creatinine-based equation known as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, using the same variables with MDRD-4 formula, has been proposed, but its superiority in patients with cirrhosis has not as yet been proven [38]. To demonstrate the variation in egfr in clinical practice in our clinical case (Table 3), the egfr ranged from 64 to 111 ml/min (Table 3). Nevertheless, these formulae do not overcome the limitations in serum creatinine measurement. It has been recommended that creatinine results used for calculating egfr should be traceable to an IDMS reference method and new Table 3. Estimation and measured renal function (GFR) in a 52-year-old man admitted with chronic liver disease and ascites secondary to alcohol a Method/equation GFR ml/min/1.73m 2 Cockcroft Gault MDRD MDRD-4 revized 64.0 MDRD CKD-EPI 72.0 Hoek equation (Cys C) cr EDTA clearance (bolus) 47.0 Inulin clearance (infusion) 54.0 a Weight kg, height 1.79 m, enzymatic serum creatinine 103 lmol/l (1.17 mg/dl), serum urea 10 mmol/l (28.1 mg/dl), plasma Cys C of 1.67 mg/l, albumin 33 g/l, bilirubin 161 lmol/l (9.4 mg/dl), normalized international ratio 1.4. See text for references. methods have been developed for the faster and simpler quantification of creatinine but require further validation [39]. However, it should also be remembered that these equations were derived in patients without cirrhosis. Estimates for egfr are also unreliable in AKI and muscle wasting disorders due to different kinetics for creatinine generation and accumulation. Alternative methods for assessing renal function in patients with cirrhosis Cystatin C. Serum cystatin C (CysC) is a low-molecular weight protein functioning as an extracellular inhibitor of cysteine proteases. It was initially thought that Cys C was produced at a stable rate by all nucleated cells, released into the blood and then freely filtered by the renal glomeruli and subsequently metabolized in the proximal tubules. Given these features, CysC was proposed as a surrogate marker for GFR. Furthermore, based on its reported independence from the effects of age, gender and body composition, it has been considered as a more sensitive indicator of renal function compared to creatinine, in several disease groups including cirrhosis [40, 41]. Over the last few years, a number of CysC-based GFR equations have been developed but all from non-cirrhotic cohorts of patients [42 44]. Although they proved to be more accurate than Cr-based formulas [45], they still lacked significant correlation with direct methods of measuring GFR. Indeed, it is now realized that CysC has greater diurnal intrapatient variability than creatinine [46] but is not affected by meals [47]. Cys C has been reported to be affected by a host of factors including inflammation [48], age [49], sex, race, body composition, proteinuria, cardiovascular risk factors [50, 51], infection, thyroid dysfunction, underlying malignancy, smoking and a number of drugs; including corticosteroids, cotrimoxazole, angiotensin-converting enzyme inhibitors and calcineurin inhibitors. In addition, CysC measurements vary just as with creatinine between assays provided by different manufacturers [52] but also intra-assay variation [53]. As such, there has been a recent move to standardize Cys C-based assays [54]. CysC has been proposed as a marker of liver disease stage [41] as it correlates with bilirubin, albumin, international normalized ratio (INR) and platelet count and increases with CTP stage [55, 56]. As cirrhosis evolves, the increasing CysC values may be related to increased production, secondary to active inflammatory and fibrotic processes or decreased clearance due to reduced renal function [56, 57]. One study validated CysC GFR in 44 patients with Child- Pugh B and C cirrhosis, using the Larsson and Hoek equations; comparing these with the MDRD4 and C-G formulae and inulin clearance as the gold standard [56]. All egfr formulas significantly overestimated the true GFR. Data from our own centre again showed that CysC GFR overestimated GFR compared to that obtained with 51 Chromiumlabelled ethylenediaminetetraacetic acid (EDTA) [56]. In our cohort, the Hoek CysC formula performed better than the Larsson equation, being the less biased, and better than the creatinine-based MDRD. Multivariate analysis showed that the presence of ascites significantly affected serum Cys C values. Although each CysC formula overestimated renal

5 Nephrol Dial Transplant (2011): Editorial Review 2739 clearance significantly in comparison to 51 Cr-EDTA for the subgroup of patients with a measured EDTA GFR of <70 ml/min/1.73m 2, as an assessment of method bias and accuracy the percentage of cystatin-based results within (either above or below) 10% (P10), 30% (P30) and 50% (P50) of the EDTA measured clearance were 23, 42 and 53% for Hoek and 15, 46 and 73% for MDRD, respectively. Whereas in comparison, in a study based on a cohort of patients with chronic kidney disease (GFR <30 ml/min/1.73m 2 ), the P30 and P50 were much better being 69 and 88%, respectively, for the MDRD formula [58]. Thus showing greater divergence in egfr assessments in patients with cirrhosis, although Cys C measurements are less likely to overestimate GFR at higher clearances (Table 3). The results from current studies suggest that although serum CysC tends to reduce the overestimation of GFR using creatinine-based methods, it is unclear whether CysC provides any significant advantage in assessing renal function in patients with cirrhosis, and CysC assays are more expensive. Isotopic and iodinated radiocontrast methods Exogenous markers, which are only cleared by the kidney, are typically considered to be more accurate methods for determining renal function. These include synthetic polyfructosans, radiolabelled compounds ( 51 Cr-EDTA, 99m Tc- diethylenetriamine pentaacetate and 51 I-iothlamate) or non-radioactive agents (iohexol or iothalamate) have been used [59, 60]. Typically, a single-bolus administration is used for ease of use, resulting in an initial peak with redistribution associated with a monoexponential fall in plasma concentration as some of the exogenous marker passes from the vascular compartment to the interstitial space (Figure 2), which is then followed by a linear decline. Clearance can then be calculated by measuring the concentration of the isotope or marker in plasma with correspondingly timed urine collections. However, errors arecommonlyreportedwhentimed urinary collections are used, with a wide range of interpatient variation reported [61, 62]. An alternative is to simply use repeated blood samples taken 3 6 h after bolus administration to construct a linear decay line, which is then extrapolated backtothetime of bolus administration and the GFR calculated from the area Fig. 2. Cartoon depicting the decay curve following a bolus injection of 51 chromium-labelled EDTA and the effects of extracellular fluid volume expansion and ascites. under the curve. As the area under the line is less than that under the actual decay curve, many laboratories use a correction factor to account for the greater area under the curve during the redistribution phase. Studies have shown that multiple sampling provides more accurate assessment of GFR than single sampling [63], particularly when the GFR is <40 ml/min [64]. Potentialerrorswithsingle-bolusadministrationcanoccur in patients due to extrarenal clearance and or redistribution of tracer from the plasma volume, leading to an overestimation of plasma clearance compared to renal plasma clearance by ~3.7 ml/min [65]. This effect can be increased in patients with expanded vascular and extracellular fluid compartments with the decay curve shifted upwards. In cirrhotic patients with ascites, there is initial redistribution of contrast dye or radionucleotide tracer into the ascitic fluid, with a faster initial fall in plasma isotope concentration (Figure 2), and then as the marker returns from the ascitic fluid back into the plasma, the slope of the steady part of the decay curve is slower (Figure 2). The effect on GFR measurement depends on the relative change of the decay curve slope and the intercept, which varies unpredictably between patients, and may be related to ascitic and extracellular volumes. As such, bolus administration of exogenous markers has been reported to overestimate GFR in patients with cirrhosis by up to 20 ml/min [65], although this can be overcome by taking delayed samples and a late 24 h sample to allow time for adequate equilibration. To exclude these errors, studies have shown that inulin clearance using a constant infusion technique is more reliable than bolus administration [66]. Although inulin is a relatively small molecule and readily redistributes into ascites it may then take several hours to fully reequilibrate and achieve a constant plasma concentration. These potential errors in estimation of GFR are then compounded when the GFR is corrected for body surface area, as this assumes a normal underlying body composition, whereas patients with cirrhosis and ascites typically have protein energy wasting in keeping with other chronic diseases [67, 68]. Thus, most studies have shown that these radiocontrast dye and isotopic nucleotide method also tend to overestimate renal function when compared to inulin clearance measured by infusion [66] rather than bolus technique [69]. However, the constant inulin infusion technique is based on a stable plasma inulin concentration so that inulin recovered in timed urine collections can be used to estimate GFR. This gold standard technique is, however, time consuming, as equilibration in patients with chronic liver disease and ascites may take >8 h, costly and potentially invasive if bladder catheterization is required. However, isotopic bolus and constant infusion techniques do not overestimate renal function compared to creatinine-based methods (Table 3). After estimating the GFR, this is then traditionally corrected for body surface area based on standard equations, which assume a fixed ratio of muscle mass to body surface area [70, 71]. Although correction factors can be used to compensate for sex, age [72] and race [73], these equations basically assume a normal distribution of body fat and muscle, whereas patients with cirrhosis have increased weight due to ascitic fluid (an unknown variable) but also loss of body fat and muscle mass consequent upon chronic liver

6 2740 Nephrol Dial Transplant (2011): Editorial Review disease and protein energy wasting, so adding additional errors to the estimation of GFR. Renal clearance determined after infusion of a GFR marker (inulin, contrast media or EDTA) to a constant plasma level is probably the more accurate technique to ensure a reliable GFR estimation, so eliminating errors from urine collections. Although extending the standard time sampling and including a delayed (24 h) sample can improve the accuracy of singlebolus administration. Summary In every day clinical practice, renal function is assessed by serum creatinine estimation throughout the world. Serum creatinine and changes in creatinine are used to define acute kidney and in cirrhotic patients HRS [74] and priority waiting times for liver transplantation. There is no universal standardized creatinine assay or readily available IDMS-traceable standards for patients with liver dysfunction or cirrhosis. The colourimetric Jaffe assay is prone to errors not only due to non-renal patient factors (age, sex, muscle mass, diet) but also interference from bilirubin and other compounds [75]. Patients with the same underlying true renal function may well have different serum creatinine values reported, resulting in different MELD scores, so changing priority for liver transplantation and also selection of treatment for HRS [72]. Unfortunately, other simple renal biomarkers, such as Cys C, also appear to have errors [73]. Inulin clearances are impracticable in routine outpatient clinical practice, as are single bolus isotopic and iodinated radiocontrast methods relying on timed urinary collections [76]. However, serial plasma measurements, in particular with delayed sampling to allow equilibration between plasma and the extracellular space, particularly ascitic fluid, would provide a more accurate estimate of GFR. However, errors would occur when trying to correct for body surface area using standard equations based on a healthy population. The question arises as to whether creatinine-based methods can be improved. Greater standardization of creatininebased assays is required to improve reliability of results; and IDMS-traceable standards improves quality control but even so could not adjust for interfering chromogens, such as bilirubin. Enzymatic creatinine assays have least bias [23] but generally remain more expensive than the compensated Jaffe assays [20]. Adjustment for muscle mass or lean body mass improves the reliability of creatinine based methods [77] Although lean body mass is more difficult to measure in clinical practice [67, 68] than simple height [78], prospective studies are required to investigate whether such adjustments improve the reliability of not only creatinine-based assays but also Cys C in cirrhotics. Conflict of interest statement. None declared. References 1. 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