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Evaluation of renal function in patients with cirrhosis
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Articles in Press
Jnl of Hepatology June 2010
it can be reasonably assumed that diabetic nephropathy is a relatively frequent cause of impaired renal function in cirrhosis
Evangelos Cholongitas, Elias Xirouchakis, Matteo Garcovich, A.K. Burroughs
The Royal Free Sheila Sherlock Liver Centre and University, Department of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK Tel.: +44 20 74726229; fax: +44 20 74726226
Received 17 February 2010; accepted 21 February 2010. published online 24 March 2010.
Corrected Proof
To the Editor:
We read with great interest the excellent review by Francoz et al. [1], recently published in the Journal of Hepatology, regarding the difficulties in the accurate assessment of renal function in patients with cirrhosis. This has become even more important and necessary in the MELD era. The main message is in keeping with our previous review [2], that is that although serum creatinine (Cr) is a routine laboratory test and widely accepted as a measure of renal function, it is only an indirect marker of renal function, i.e. of glomerular filtration rate (GFR). Indeed, a problem, not often recognized by hepatologists, is that measurement of Cr suffers from a variety of interferences [3]. In particular, in patients with cirrhosis, we have shown that the interference of bilirubin on Cr measurement is a major problem leading to differences in MELD scores up to seven points when bilirubin is higher than 23.4mg/dl, i.e. those with the highest priority for liver transplantation [3]. Francoz et al. [1] mentioned that several methods have been developed in order to overcome this interference, but we have shown that the problem has not been resolved [3]. Furthermore, using different methods of measurement leads to further discrepancy in Cr values [3], [4]. Hence, standardisation of laboratory techniques and 'normal' values would have to be undertaken for all liver transplant units to avoid systematic biases in MELD-based allocation systems, or those which incorporate Cr values [4].
Apart from difficulties in measurements, it is well recognized that Cr concentration is influenced by several factors unrelated to renal function, such as total muscle mass. The latter can lead to discrepancies in Cr concentration between individuals with the same renal function but of different age, race, and sex [5]. This important issue was not emphasized in this review [1]. In the UNOS database [6], it has been shown that women were more likely to die on the waiting list in the post-MELD era, compared to the pre-MELD one, although women were listed with lower median MELD scores, compared to men (14 vs. 15, p<0.001) [6]. These findings are likely to be due to the fact that women have lower Cr for the same renal function (GFR), compared to men, as we have published previously [7]. Interestingly, we found that correcting Cr by equalising the GFR between men and women resulted in an increase in MELD score by 2 or 3 points in 65% of female LT candidates [7]. Our findings with gender influences on Cr measurement are also pertinent to ethnicity differences with a lower GFR for the same Cr value in those of Asian ethnicity and conversely a higher GFR for those of African descent. Thus, a correction factor for gender and ethnicity could be introduced.
Alternatively, the use of "true" GFR could be considered in order to eliminate any gender or race bias. Interestingly, Lim et al. [8] in the same Journal found that GFR (estimated by using 125I-iothalamate) was superior to Cr in assessing mortality risk on the waiting list. Its incorporation in the MELD score (in the place of Cr), led to a relatively small, but nevertheless, significant improvement of discriminative ability of MELD. Unfortunately, Lim et al. [8] did not evaluate the prognostic impact of MELD-Cr and MELD-GFR scores in male and female candidates separately. However, directly measured GFR is expensive and impractical for routine use, and thus, identification of more accurate and clinically applicable serum markers for renal function in cirrhosis are necessary and could remove the bias of Cr in the MELD score. Similar to our conclusions in our review [2], Francoz et al. [1] suggested cystatin-C as an alternative marker of renal function. However, cystatin-C has its own limitations and we have found that the available data on cystatin-based formulae have poor agreement with "true" GFR in patients with cirrhosis [9]. The inaccuracy of these mathematical equations may be related to the fact that the original cohorts from which they were derived did not include patients with cirrhosis. We believe that new equations are needed in patients with cirrhosis to reflect "true" GFR as accurately as possible.
The evaluation of renal function and disease in patients with cirrhosis
Pages 605-613 (April 2010)
Claire Francoz1, Denis Glotz2, Richard Moreau1, Fran¨ois Durand1Corresponding Author Informationemail address
Received 16 September 2009; received in revised form 17 November 2009; accepted 20 November 2009. published online 07 January 2010.
The MELD score has shown that, besides markers of liver function, serum creatinine has a strong prognostic value in cirrhosis. However, even though creatinine has a good prognostic value, it is an inaccurate marker of renal function in cirrhosis. Creatinine and creatinine-based equations tend to overestimate glomerular filtration rate (GFR), and creatinine clearance from timed urine collection also overestimates GFR. Hence, clearance of exogenous markers such as iohexol remains the only reliable method for assessing precisely GFR in cirrhosis. Whereas these investigations are limited by their costs and complexity, and they can hardly be repeated at short intervals, serum cystatin C could be an alternative, although it needs further validation. Accurate markers and/or specific equations are therefore still needed to assess GFR in cirrhotic patients. Pre-renal failure and hepatorenal syndrome (HRS) are the main causes of acute renal failure in cirrhosis. Both result from decreased renal blood flow and both can result in acute tubular necrosis. HRS is not always fully reversible with liver transplantation possibly due to underlying chronic kidney damage. A number of cirrhotic patients with acute renal failure may also have chronic kidney damage ("acute-on-chronic renal failure"); furthermore, cirrhotic patients frequently have co-morbidities such as diabetes that may result in chronic impairment in renal function. Since conventional urinary markers are biased in cirrhosis, a biopsy is the only way to document and quantify renal lesions; moreover, transvenous route should be preferred to percutaneous route. In candidates for transplantation, attention should therefore be focused on vascular lesions which may represent a risk factor for nephrotoxicities induced by calcineurin-inhibitors.
"Conclusions and perspectives - Physicians involved in the care of patients with cirrhosis have become even more interested in the assessment of renal function as, with the advent of MELD score, creatinine was shown to be a strong prognostic marker. However, in cirrhosis, there is still a gap between serum creatinine and renal function. Serum creatinine and the widely used creatinine-based equations must be interpreted with caution. In general, true GFR is lower than that expected on the basis of creatinine-based equations. Until now, direct measurement using exogenous markers is the only reliable method to quantify GFR. The reasons why creatinine-based equations are inaccurate should be clarified with the aim of overcoming inaccuracies. Further studies should be conducted in large series of cirrhotic patients to correlate true GFR to potential markers. Only such studies could result in the creation and validation of more specific equations for cirrhotic patients. Whether this goal can be better achieved with creatinine or with other endogenous markers such as cystatin C needs further investigations. An improvement in the assessment of baseline renal function, especially in cirrhotic patients who may have fluctuations in GFR over time, could result into more accurate prognostic tools. Even if it is a relatively inaccurate marker of renal function in cirrhosis, serum creatinine which has a strong prognostic value can be used in routine.
Besides the assessment of renal function, other important issues need to be addressed in the context of cirrhosis. Firstly, the mechanisms involved in chronic impairment in renal function during cirrhosis should be clarified. Secondly, the potential reversibility of impaired renal function is an especially important issue in candidates for transplantation. Identifying and quantifying renal lesions is mandatory for addressing these issues. There is no reliable alternative to invasive assessment, including renal biopsy. In the future, attempts should be made to correlate non invasive biomarkers of kidney damage [94], [95], [96] to pathological findings. The potential contribution of renal artery Doppler ultrasonography in the detection of early increase in vascular resistance should be further investigated [50], [97]. At present, accurate assessment of renal function and lesions in cirrhotic patients is necessarily costly, time consuming and invasive. More simple and non invasive alternatives are needed."
The determinant impact of serum creatinine on the prognosis of cirrhosis
For more than 30years, the Child-Pugh score has been the main prognostic tool for patients with cirrhosis [1]. The Child-Pugh score was based on 5 variables (i.e., ascites, encephalopathy, serum bilirubin, serum albumin and prothrombin time) which had been empirically selected because they were felt to have a determinant impact on the outcome. This score proved to be a robust prognostic tool in a number of situations [2]. However, it had some limitations, including the subjective interpretation of ascites and encephalopathy. In the early 2000s, the model for end-stage liver disease (MELD) score emerged as a simple, more objective, alternative to Child-Pugh score [3], [4], [5]. The 3 variables entered in the MELD score have been selected on the basis of statistical analysis, not empirically. The weight associated to each of the variables also derives from statistical analysis. Interestingly, besides serum bilirubin and international normalized ratio (INR) which are basic markers of liver function, the third component of the MELD score, serum creatinine, is essentially a marker of renal function. This finding highlights the prognostic significance of the interactions between liver function and renal function in cirrhosis. The value of creatinine weighs heavily on the MELD score [5]. As an example, an increase in serum creatinine from 1 to 1.5mg/dl (88 to 132µmol/L) in a patient with a bilirubin of 2.9mg/dl (50µmol/L) and an INR of 1 results in a 40% increase in the MELD score.
The MELD score has been widely validated in different populations of cirrhotic patients [6]. However, it has been suggested recently that creatinine weighs too heavily on the MELD score [7]. In addition, it has been pointed out that patients with serum creatinine below 1mg/dl are bounded to 1mg/dl in order to avoid negative values after logarithmic transformation. A relatively large number of cirrhotic patients have baseline serum creatinine below 1mg/dl and some of them have significant impairment in renal function. The assumption that mortality is constant for creatinine less than 1mg/dl is likely to be false. As a result, a modified MELD score including loge (1+creatinine [mg/dl]) without bounding and a lower weight for creatinine compared to the current MELD score has been proposed [7]. This modified score seems to be slightly superior the current MELD score. However, even after these adjustments, creatinine still has a determinant prognostic value.
From serum creatinine to renal function in cirrhotic patients: many sources of discordance
Creatine is the simplest and the most widely used marker of renal function in the general population. However, it is a paradox that even if creatinine is a powerful prognostic marker in cirrhosis, it is an inaccurate marker of renal function in most cirrhotic patients. Indeed, in these patients, there are many biases and pitfalls in the interpretation of creatinine as well as creatinine-based estimates of renal function.
Interpretation of serum creatinine
Creatine is synthesized in the liver before being stored in muscles where it is phosphorylated as creatinine. The production of creatinine varies little from day to day. This small compound is freely filtered by the kidney but it can also be secreted by the proximal tubule. The ratio between creatinine secreted by the tubule to the amount of creatinine filtered by the glomerulus increases as glomerular filtration rate (GFR) decreases. In addition to muscle mass and protein intake, creatinine is influenced by age, gender and ethnicity.
Several reasons make that in cirrhotic patients, serum creatinine may overestimate renal function. Impaired liver function results in decreased creatinine production. Protein-calorie malnutrition and muscle wasting which are common during cirrhosis [8], [9] also contribute to decreased creatinine production. On average, baseline serum creatinine is lower in cirrhotic patients compared to the general population [10], [11]. Baseline serum creatinine within the normal range does not exclude a significant impairment in renal function [12], [13], [14], [15]. Patients may present a twofold increase in baseline creatinine with levels remaining below 1mg/dl (88µmol/L), apparently within the normal range. Another bias comes from fluctuations of serum creatinine, especially in those with refractory ascites and/or those receiving diuretics. Wide variations may be observed, depending on large volume paracentesis and volume expansion. In such situations, the issue of which serum creatinine value is best correlated to the outcome is difficult to address.
Significant inter-laboratory variations may be observed in the dosage of creatinine, mainly due to an interaction with bilirubin [16], [17]. Routine creatinine dosage is based on spectrophotometry. In patients with jaundice, bilirubin as a chromogen interferes with creatinine dosage, resulting in falsely low creatinine values. The higher is serum bilirubin, either conjugated or unconjugated, the higher is the interference. It has been shown that inter-laboratory variations may impact on MELD score [18]. For example, when four different methods of creatinine dosage are applied in patients with serum bilirubin between 200 and 400µmol/L, a difference in MELD score >2 points may be observed in about 60% [18]. Several techniques such as deproteinization, the use of bilirubin oxidase or kinetic alkaline picrate methods may help overcome this interference [19], [20]. However, the dosage of serum creatinine has not been standardized.
On an individual basis, serum creatinine should be interpreted with caution in cirrhotic patients due to frequent overestimation of renal function. Overestimation is especially high in patients with advanced liver disease, high bilirubin and refractory ascites. Therefore, creatinine alone is insufficient for identifying either acute or chronic renal disease in these patients.
Creatinine clearance from timed urine collections: friend or foe?
In theory, creatinine clearance from timed urine collections might be a reliable method for assessing renal function. However, several studies have shown that, in cirrhotic patients, creatinine clearance, when compared to inulin clearance as the reference standard, overestimates true GFR by a mean of about 13ml/min/1.73 m3 [15], [21], [22], [23]. Overestimation is highest in patients with low GFR [23].
The reasons for the discordance between creatinine clearance and true GFR could be related, at least in part, to the increased proportion of creatinine secreted by the tubule compared to creatinine filtered by the glomerulus during cirrhosis, especially in those with low GFR [22]. From a practical view point, non specific factors including incomplete urine collection and errors in the timing of collection may play a more difficult to identify role in the inaccuracy of creatinine clearance.
Creatinine clearance based on timed urine collections, even if well conducted, is not the guarantee of an accurate assessment of renal function in cirrhotic patients. Overestimation may lead to inappropriate classification and/or therapeutic adjustments in about 50% patients [23]. There is no evidence that creatinine clearance is preferable to serum creatinine.
Creatinine-based equations: definitely foe
The creatinine-based Cockcroft and MDRD equations are widely used in the general population to estimate GFR [10], [11]. MDRD is considered the gold standard in nephrology [24]. However, as these equations are based on serum creatinine, it is not surprising that they are also inaccurate in cirrhotic patients. Several studies have shown that both Cockcroft and MDRD tend to overestimate true GFR [12], [14], [22], [25]. The largest series has shown that only 66% of estimates were within 30% of the measured GFR [26]. In cirrhotic patients, MDRD which does not take into account body weight seems to be less inaccurate than Cockcroft [26]. Indeed, body weight may be markedly biased in patients with oedema and/or ascites. However, the accuracy of MDRD, even if slightly superior to that of Cockcroft, remains limited [12].
The inaccuracy of Cockcroft and MDRD in cirrhotic patients may be related to several factors. As discussed above, creatinine is an inaccurate marker of renal function in this population. In particular, normal serum creatinine does not exclude a marked decrease in GFR. Secondly, Cockcroft and MDRD equations include serum creatinine adjusted for several variables which were shown to have a significant impact on GFR in the general population (i.e., age, body weight and gender for Cockcroft; age, gender and ethnicity for simplified MDRD). The factors associated with each of these variables are not necessarily well suited for cirrhotic patients. Different adjustments could be needed. Finally, Cockcroft and MDRD are not adjusted for some variables which are likely to have a determinant impact on the estimation of GFR in cirrhotic patients. For example, body weight is difficult to interpret without taking into account ascites and oedema.
Recently, a new creatinine-based equation termed CKD-EPI (for Chronic Kidney Disease Epidemiology Collaboration), adjusted for gender and ethnicity has been proposed as a more accurate formula compared to Cockcroft and MDRD [27]. This formula has not been tested in cirrhotic patients yet. However, as it is also based on serum creatinine, it can be anticipated that CKD-EPI is not markedly superior to other creatinine-based equations in cirrhosis.
Creatinine-based equations should not be recommended to estimate renal function in cirrhotic patients. Indeed, these formulas may give falsely reassuring values since they tend to overestimate GFR. More data are needed to create and validate more specific equations with an acceptable accuracy in cirrhosis. To date, no such equations have been proposed.
Alternatives to creatinine and creatinine-based equation for the assessment of renal function
Clearance of exogenous markers
Direct measurement of GFR using exogenous markers remains the reference to assess renal function in cirrhotic patients. Direct measurement of GFR is mandatory to precisely assess renal function and adequately classify patients into the different categories of impaired renal function (Table 1) [28].
Inulin clearance has been considered the "gold standard". Inulin is freely filtered by the glomerulus and not secreted, reabsorbed, synthesized or metabolized by the kidney. Consequently, for a stable concentration of inulin in the plasma, the amount of filtered inulin by the glomerulus is equal to the amount excreted in the urine [29]. However, this technique requires a continuous intravenous infusion and timed urine collections over a period of several hours. This technique is time consuming, costly and potentially invasive if bladder catheterization has to be done for urine collection. Other techniques using markers such as synthetic inulin-like polyfructosans, radiolabeled compounds (51Cr-EDTA, 99mTc-DPTA and 125I-iothalamate) or non-radioactive agents (iohexol or iothalamate) have been proposed [24], [30]. The main advantage of these markers is a single-injection with measurement of GFR based on the total area under the curve of the plasma concentration of the marker. Time collection of urine samples is not needed. The use of radiolabeled compounds is limited by exposure to radiation and costs. Contrast agents seem to be safer even though rare allergic events have been reported. None of these alternative techniques have been specifically validated in cirrhosis. However, since markers are exogenous and only eliminated by the kidney, it can be assumed that their accuracy is similar to that of inulin clearance. Measurements using iohexol or iothalamate can be recommended. However, these techniques which are technically demanding and costly can hardly be repeated at close intervals.
Cystatin C and other markers
Recently, it has been shown that serum cystatin C, another endogenous marker, could represent an interesting alternative to serum creatinine [24]. Cystatin C is a low molecular weight protein produced at a constant rate by all nucleated cells and eliminated almost exclusively by glomerular filtration [31]. After filtration, cystatin C is reabsorbed and catabolized by the tubular epithelial cells. Consequently, urinary clearance cannot be measured [24], [32]. In contrast to creatinine, serum cystatin C is independent of gender, age and muscle mass. The dosage is not influenced by serum bilirubin, inflammation or malignancy [33], [34]. A recent meta-analysis has shown that, in non-cirrhotic patients, cystatin C is better correlated with GFR than creatinine [35]. Interestingly, it has been shown that the sensitivity of cystatin C for the diagnosis of impaired renal function, with a cut-off value of 1.25mg/dl, is similar in cirrhotic patients and in non-cirrhotic patients [21]. Several small studies have suggested that, after kidney or liver transplantation, serum cystatin C could be useful to monitor renal function [36], [37], [38], [39]. Finally, several equations using serum cystatin C have been proposed to estimate GFR [40], [41], [42]. Although serum cystatin C is easy to obtain routinely, it has several limitations. Firstly, the cost of the assay is significantly higher compared to serum creatinine. Secondly, the assays need further standardization [32]. Thirdly, serum cystatin C is influenced by infection and by some drugs such as corticosteroids, angiotensin-converting enzyme inhibitors or calcineurin inhibitors (CNI) [43], [44]. It has been suggested that cystatin C could be a marker of progression of liver fibrosis [45], [46]. This could represent a potential bias for the assessment of renal function in cirrhotic patients. However, there is no evidence that the increase in cystatin C in patients with fibrosis is not correlated to changes in renal function [46].
Apart from cystatin C, other biomarkers, such as β2 microglobulin or β-trace protein have been proposed. They do not seem to be accurate enough for estimating renal function [34].
Renal Doppler ultrasonography
Hepatorenal syndrome (HRS) is characterized by renal vasoconstriction. Renal vasoconstriction has been documented in several series of cirrhotic patients by Doppler ultrasound (US) analysis of renal arteries, showing increased resistive index (RI) [47], [48], [49]. RI is determined from the spectral waveforms and corresponds to the following formula: (peak systolic frequency shift - lowest diastolic frequency shift)/peak systolic frequency shift. On average, renal RI is higher in cirrhotic patients compared to healthy individuals and high RI (over 0.7) can be observed in cirrhotic patients with serum creatinine within the normal range [47]. In patients without refractory ascites, RI decreases from the hilum towards the outer parenchyma, suggesting that the flow to the cortex is relatively preserved [47]. In contrast, in patients with refractory ascites, RI is also increased in the cortical vessels suggesting cortical vasoconstriction. Paracentesis and albumin infusion are followed by a significant decrease in renal RI [48]. Liver transplantation is also followed by a decrease in RI [50].
In patients with normal serum creatinine, increased RI seems to be correlated with a higher risk of subsequent deterioration in renal function [50]. Therefore, Doppler ultrasound may be an early marker of renal dysfunction. In candidates for transplantation, high renal RI is associated with a greater risk of renal dysfunction and dialysis post-transplantation [49]. However, in cirrhotic patients with impaired renal function, whether high RI predicts complete recovery is unclear.
Overall, Doppler US may be useful for identifying patients at high risk for developing impaired renal function at an early stage. It may be useful for clarifying the mechanisms involved in renal insufficiency. It may help clarify the role of therapeutic intervention on renal hemodynamics. However, RI is not correlated to GFR [51]. In addition, there is no evidence that Doppler US helps differentiate cirrhotic patients with impaired renal function only related to vasoconstriction from patients who have both vasoconstriction and intrinsic kidney damage.
Facing the spectrum of causes of impaired renal function in cirrhosis
Once impaired renal function has been documented, an important step is to determine its causes and mechanisms. It may be a difficult issue to address given that, in the context of cirrhosis, impaired renal function may result from several cofactors. In addition, patients with chronic renal damage and baseline impairment in renal function may present with superimposed acute renal injury ("acute-on-chronic renal failure").
Acute renal failure
The two main causes of acute renal failure in cirrhosis are functional (pre-renal) renal failure and HRS type I [52]. The administration of nephrotoxic agents (aminoglycosides and non steroidal anti-inflammatory drugs, among others) and aggressive diuretic therapy also represent possible causes of acute renal failure or contributing factors (Table 2) [52], [53], [54].
Table 2. Main causes of acute and chronic kidney diseases in patients with cirrhosis.
Acute kidney diseases
Hepatorenal syndrome (type I)
Pre-renal (functional) failure
Acute tubular necrosis
Following hepatorenal syndrome
Following pre-renal failure
Drug-induced (amlinoglycosides, non steroidal anti-inflammatory drugs)
Osmotic tubulopathy (contrast agents, hydroxyethyl starch)
Chronic kidney diseases
Diabetic glomerulosclerosis
Ischemic nephropathy
Alcohol-related IgA nephropathy
HCV-related membranoproliferative glomerulonephritis
HBV-related membranous ne phropathy
Non-diabetic glomerulosclerosis
Hepatorenal syndrome (type II)
This list is not exhaustive.
Occasionally, type 2 hepatorenal syndrome may progress to end stage renal disease in less than 3 months.
Pre-renal failure can be precipitated by hypovolemia (following variceal bleeding for instance) and sepsis [55], [56], [57]. Although pre-renal failure and acute tubular necrosis can occur at any stage of cirrhosis, HRS essentially occurs in patients with advanced liver insufficiency and/or refractory ascites [58]. Basically, pre-renal failure and HRS result from the same mechanism, namely, a marked decrease in renal blood flow. During HRS, the decrease in renal blood flow is secondary to renal vasoconstriction. If reduced renal blood flow persists, both pre-renal failure and HRS may eventually lead to acute tubular necrosis. However, the occurrence of acute tubular necrosis following prolonged renal vasoconstriction has not been clearly documented on a pathological basis. When patients with HRS develop acute tubular necrosis, the degree of renal vasoconstriction tends to worsen due to intense activation of the tubuloglomerular feedback and reflective afferent arteriolar vasoconstriction [59]. Eventually, prolonged renal ischemia leads to glomerular and interstitial fibrosis with irreversible consequences [60].
A first set of criteria has been proposed in 1996 for the diagnosis of HRS [61]. These criteria were complex and restrictive. In patients with advanced cirrhosis the occurrence of "functional-like" acute liver failure is frequently triggered by sepsis or some degree of hypovolemia. Therefore, it was unlikely that patients with HRS could meet all the criteria. The diagnostic criteria have been revised recently in order to be less restrictive and more flexible in clinical practice (Table 3) [62]. However, it can be objected that the revised criteria are not specific enough and that the frontier between functional renal failure and HRS in patients with end-stage cirrhosis becomes artificial. In a context of end-stage cirrhosis associated with complications including acute renal failure, the identification of HRS as a specific disease entity may still be difficult.
Chronic kidney diseases
Type 2 HRS is characterized by a steady or slowly progressive course compared to type 1 HRS which progresses rapidly [63]. It has been defined empirically as a moderate increase in serum creatinine ranging from 1.25mg/dl and 2.5mg/dl (110-220µmol/L) with a less progressive course than does type 1 HRS [61]. Type 2 HRS is usually associated with refractory ascites and, even if liver function is relatively preserved, the prognosis is poor [64], [65]. Type 2 HRS is most often considered a cause of chronic kidney disease in patients with cirrhosis. However, this classification may be misleading as some patients with type 2 HRS can progress to end-stage renal disease in less than 3months. Renal vasoconstriction and decreased renal blood flow seem to be pivotal in the development of type 2 HRS. Prolonged renal hypoperfusion may result in chronic injury. Importantly, whether type 2 HRS is purely a functional and potentially reversible disorder or corresponds to underlying chronic renal lesions of various origin needs to be clarified.
Independent of hypoperfusion and ischemia, patients with cirrhosis frequently have diseases or comorbidities which may determine chronic renal injury. The main causes of chronic renal diseases in patients with cirrhosis are listed in Table 2. The distribution of each of these causes has not been documented yet. However, about 60% of cirrhotic patients have impaired glucose tolerance [66]. The incidence of diabetes mellitus may be as high as 25% in patients with HCV-related cirrhosis [67]. Therefore, it can be reasonably assumed that diabetic nephropathy is a relatively frequent cause of impaired renal function in cirrhosis. Even though hypertension is highly uncommon during cirrhosis, atherosclerosis associated with glomerulosclerosis may also be relatively frequent. As an example, 20-25% of candidates for transplantation have significant coronary artery disease at evaluation, which illustrates the high incidence of atherosclerotic changes [68], [69].
The identification of the cause of renal dysfunction is important as the natural history and rate of progression to end-stage renal disease (ESRD) is variable. For example, diabetic glomerolusclerosis in patients with type I diabetes mellitus progresses more rapidly than IgA nephropathy [70]. However, even if the cause has been identified, assessing the prognosis may be a difficult issue. Patients with advanced cirrhosis are more likely to have several factors contributing to chronic renal changes than a single cause of renal disease. This assumption is supported by the frequent finding of a combination of various glomerular changes in unselected cirrhotic patients undergoing renal biopsy during liver transplantation [71], [72]. Interestingly, even patients with apparently preserved renal function may exhibit significant glomerular changes [73].
The usefulness of conventional urinary markers in the identification of the cause of kidney injury is limited. As well as in patients with acute renal failure, the interpretation of urinary sodium, fractional excretion of sodium and urine osmolality may be biased by the underlying activation of water and sodium retention systems, recent or ongoing administration of diuretics and volume expansion. The usefulness of proteinuria is also limited, possibly due to low serum protein level. Several reports have clearly shown that normal quantitative proteinuria does not exclude glomerular changes [73], [74]. In most of the cases, the objective is to document and quantify renal lesions (i.e., glomerular, vascular and/or tubulo-interstitial) rather than to identify a specific cause of renal disease. As far as reliable non invasive markers are identified and validated, this end can only be achieved by renal biopsy.
The place of renal biopsy
In patients with acute renal failure, renal biopsy is rarely needed since, as discussed above, the main causes of acute renal failure are pre-renal failure and HRS. Characterisation of renal lesions, if any, is not useful for the management of these conditions. In contrast, renal biopsy may be useful in patients with chronic impairment of renal function, before the occurrence of end-stage renal disease. Pathological examination remains the only way to document and quantify renal lesions. In theory, percutaneous kidney biopsy represents the ideal route since, most often, it allows to obtain adequate tissue samples. However, a substantial proportion of cirrhotic patients have contraindications to percutaneous biopsy due to coagulation disorders. Inspired from transjugular liver biopsy, transjugular renal biopsy has been developed to overcome these limitations [75], [76], [77].
In a large series of non-cirrhotic patients, transjugular route proved as efficient as percutaneous route, with a comparable rate of success to obtain adequate samples and a comparable number of glomeruli in each sample (on average 10 for optical microscopy and 5 for immunofluorescence) [78]. In this study, the rate of complications was similar with transjugular and percutaneous routes with major bleeding occurring in about 1%. However, the rate of complications of percutaneous biopsy seems to be higher in cirrhotic patients than in non-cirrhotic patients. In one series, 18% of patients had major bleeding complications requiring blood transfusion [74]. INR above 1.5 was associated with an increased risk of bleeding. These results suggest that in cirrhotic patients with mild coagulation changes, transjugular route should be preferred to percutaneous route. Small size kidneys, poor cortical differentiation and large volume ascites may preclude this technique.
Proposed guidelines concerning the indications for renal biopsy in cirrhotic patients are listed in Table 4.
Table 4. Proposed recommendations concerning the indications for renal biopsy in cirrhotic patients.
Acute renal failure
No biopsy if pre-renal failure, HRS type I or acute tubular necrosis, except if
· abnormal duration and no recovery with specific therapy, or
· candidate for liver transplantation and suspicion of superimposed chronic kidney disease
Biopsy if suspicion of uncommon intrinsic kidney disease (systemic disease, immuno-allergic-induced drug toxicity, thrombotic microangiopathy) with potential curative intervention
Chronic kidney failure
Biopsy questionable in patients not eligible for liver transplantation. Biopsy not systematically recommended
In patients eligible for liver transplantation: indications depending of GFR
· GFR<15 ml/min/1.73 m2 : no indication
· GFR between 15 to 30 ml/min/1.73 m2 : systematic biopsy
· GFR between 30 to 60 ml/min/1.73 m2 : biopsy if suspicion of parenchymal kidney disease as indicated by proteinuria>500mg/day, microhematuria (>50 red blood cells per high power field) and / or a recognized cause of chronic kidney disease (diabetes, past history of hypertension, HBV and HCV infection)
· GFR>60 ml/min/1.73 m2 : no indication
A decision should be based on measured GFR with exogenous markers, not on estimated GFR.
Assessment of cirrhotic patients before liver transplantation
Objectives
The assessment of candidates for transplantation raises specific issues. A first objective is to assess the mortality risk, given that pre-transplant renal function predicts post-transplant survival [79], [80], [81]. A pre-transplant GFR less than 40ml/min was shown to be associated with significantly lower short-term and long-term survival [81]. A second objective is to identify patients who are likely to develop end-stage renal disease within the first years following transplantation, while receiving CNI-based immunosuppression. CNI frequently have nephrotoxic effects by inducing chronic microangiopathy and interstitial fibrosis [82], [83]. The cumulative incidence of ESRD 10years after liver transplantation is of about 20% [84]. In candidates with impaired renal function, a third objective is to determine whether renal function will improve with liver transplantation, will be stabilized or will continue to progress. In those who are at risk of experiencing further deterioration of renal function, the expected rate of progression should be estimated. Overall, patients with baseline impairment in renal function should be categorized as follows: those with reversible renal dysfunction caused by liver disease and who will recover or have sufficient improvement following transplantation; those who are at risk of delayed ESRD; and, lastly, those who will not improve following transplantation or who will rapidly develop ESRD. In the two former groups, combined liver and kidney transplantation (CLKT) is not justified even if some of these patients may occasionally need sequential kidney transplantation several years after liver transplantation. Conversely, in the last group, CLKT may be justified. On the one hand, patients who already had liver transplantation can be listed for sequential kidney transplantation at the time they eventually develop ESRD. On the other hand, if kidney transplantation has to be performed, CLKT offers several advantages. Firstly, patients undergo a single procedure. Secondly, waiting time is shorter on average. CLKT guarantees adequate renal function, without limitations in the use of CNI-based immunosuppression. Lastly, the liver has immunoprotective effects on the kidney if the donor is the same [85]. There is no consensus of the minimal interval between liver transplantation and the expected occurrence of ESRD which justifies "pre-emptive" CLKT rather than sequential kidney transplantation. However, in patients with true GFR between 30 and 60ml/min/1.73 m2, an expected interval of 2-3years to progress to ESRD seems to be a reasonable limit to consider CLKT.
A decision for CLKT should be based on direct measurement of GFR using exogenous markers (inulin or iohexol for instance); not on creatinine or creatinine-based equations. Borderline patients or patients in whom it remains difficult to distinguish the respective role of chronic and acute renal changes should undergo biopsy. Attention should focus on patients with the so called "HRS" since a substantial proportion of these patients may have underlying chronic and irreversible kidney injury. The concept of full recovery of renal function following liver transplantation in patients with HRS should be revisited. Indeed, several series have shown that even though, on average, renal function improves after transplantation, most patients have persistently high creatinine and/or decreased GFR [70], [86], [87], [88]. Patients who had HRS before transplantation develop ESRD more frequently after transplantation [70], [88]. Persistent impairment of renal function following transplantation could be due to established renal lesions secondary to ischemia and/or to underlying chronic lesions of other origin. More data are needed in this population to identify associated cofactors.
Selection of candidates for combined liver and kidney transplantation
Since the implementation of MELD score-based allocation system, the number of CLKT has dramatically increased, at least in the United States [89], [90]. Indeed, patients with high pre-transplant creatinine have a higher MELD score and, consequently, a more rapid access to transplantation. The finding that patients with serum creatinine>2mg/dl (176µmol/L) do better with CLKT than with liver transplantation alone has been an incentive to perform combined transplantation [91]. However, in the general context of organ shortage, candidates should be carefully selected in order to guarantee equity and utility.
Generally, pre-transplant dialysis in patients with acute renal failure (HRS in most cases) is not an indication for kidney transplantation. CLKT should only be considered in patients who have been on dialysis for more than 8weeks because, in this situation, recovery is highly unlikely [88], [92]. Otherwise, only patients with chronic kidney disease should be considered for CLKT. Chronic kidney disease is defined by either kidney damage or a decrease in GFR below 60ml/min/1.73 m2 for 3months or more [93]. Kidney damage is defined by pathologic abnormalities or markers of damage including abnormalities in blood or urine tests or imaging studies [93]. CLKT should be considered in patients with GFR below 30ml/min and no evidence for an additional factor related to liver disease which could improve with liver transplantation. Borderline patients should have a biopsy. It has been proposed that CLKT should be preferred to liver transplantation alone when pathology demonstrates more than 30% glomerulosclerosis and/or more than 30% interstitial fibrosis [92]. CLKT should also be considered if pathology shows prominent vascular changes since they might be at higher risk of developing ESRD with calcineurin inhibitors.
Conclusions and perspectives
Physicians involved in the care of patients with cirrhosis have become even more interested in the assessment of renal function as, with the advent of MELD score, creatinine was shown to be a strong prognostic marker. However, in cirrhosis, there is still a gap between serum creatinine and renal function. Serum creatinine and the widely used creatinine-based equations must be interpreted with caution. In general, true GFR is lower than that expected on the basis of creatinine-based equations. Until now, direct measurement using exogenous markers is the only reliable method to quantify GFR. The reasons why creatinine-based equations are inaccurate should be clarified with the aim of overcoming inaccuracies. Further studies should be conducted in large series of cirrhotic patients to correlate true GFR to potential markers. Only such studies could result in the creation and validation of more specific equations for cirrhotic patients. Whether this goal can be better achieved with creatinine or with other endogenous markers such as cystatin C needs further investigations. An improvement in the assessment of baseline renal function, especially in cirrhotic patients who may have fluctuations in GFR over time, could result into more accurate prognostic tools. Even if it is a relatively inaccurate marker of renal function in cirrhosis, serum creatinine which has a strong prognostic value can be used in routine.
Besides the assessment of renal function, other important issues need to be addressed in the context of cirrhosis. Firstly, the mechanisms involved in chronic impairment in renal function during cirrhosis should be clarified. Secondly, the potential reversibility of impaired renal function is an especially important issue in candidates for transplantation. Identifying and quantifying renal lesions is mandatory for addressing these issues. There is no reliable alternative to invasive assessment, including renal biopsy. In the future, attempts should be made to correlate non invasive biomarkers of kidney damage [94], [95], [96] to pathological findings. The potential contribution of renal artery Doppler ultrasonography in the detection of early increase in vascular resistance should be further investigated [50], [97]. At present, accurate assessment of renal functio
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