Renal dysfunction in patients with cirrhosis: Where do we stand?

Abstract

Patients with cirrhosis and renal failure are high-risk patients who can hardly be grouped to form precise instructions for diagnosis and treatment. When it comes to evaluate renal function in patients with cirrhosis, determination of acute kidney injury (AKI), chronic kidney disease (CKD) or AKI on CKD should be made. First it should be excluded the prerenal causes of AKI. All cirrhotic patients should undergo renal ultrasound for measurement of renal resistive index in every stage of liver dysfunction and urine microscopy for differentiation of all causes of AKI. If there is history of dehydration on the ground of normal renal ultrasound and urine microscopy the diuretics should be withdrawn and plasma volume expansion should be tried with albumin. If the patient does not respond, the correct diagnosis is HRS. In case there is recent use of nephrotoxic agents or contrast media and examination shows shock, granular cast in urinary sediment and proteinuria above 0.5 g daily, acute tubular necrosis is the prominent diagnosis. Renal biopsy should be performed when glomerular filtration rate is between 30-60 mL/min and there are signs of parenchymal renal disease. The acute renal function is preferable to be assessed with modified AKIN. Patients with AKIN stage 1 and serum creatinine ≥ 1.5 mg/dL should be at close surveillance. Management options include hemodynamic monitoring and management of fluid balance and infections, potentially driving to HRS. Terlipressin is the treatment of choice in case of established HRS, administered until there are signs of improvement, but not more than two weeks. Midodrine is the alternative for therapy continuation or when terlipressin is unavailable. Norepinephrine has shown similar effect with terlipressin in patients being in Intensive Care Unit, but with much lower cost than that of terlipressin. If the patient meets the requirements for transplantation, dialysis and transjugular intrahepatic portosystemic shunt are the bridging therapies to keep the transplant candidate in the best clinical status. The present review clarifies the latest therapeutic modalities and the proposed recommendations and algorithms in order to be applied in clinical practice.

Key Words: Renal dysfunction; Cirrhosis; Assessment; Management; Hepatorenal syndrome

Core tip: Close surveillance, well -classified definitions and scoring systems will be helpful in recognizing the renal dysfunction. Noninvasive biomarkers (NGAL, sCysC) reflect the prospective method in identifying kidney damage and kidney function. The acute renal function is proposed to be assessed with modified acute kidney injury network (AKIN) and the baseline renal function in stable patients with MDRD-6 formula or chronic kidney disease epidemiology collaboration Cys C-Cr equation. MBRS score or RIFLE criteria for AKI evaluation should be tried in critically ill cirrhotic patients, while in candidates for transplantation, glomerular filtration rate should be preferably measured with exogenous markers for accurate assessment of renal function. Amelioration of the underlined liver disease is very impressive in patients with alcoholic liver disease after recovery from alcoholic hepatitis, and in patients with decompensated cirrhosis due to hepatitis B virus infection after receiving antiviral therapy.

INTRODUCTION

Physicians involved in the care of patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality[1-3]. Methods for early and accurate diagnosis of acute renal failure may assist initiate specific treatment at earlier stage and improve the outcome. Patients with cirrhosis can develop three main forms of acute renal failure and may suffer also from underline chronic kidney disease. Prerenal azotemia is the basis of acute renal injury, which can trigger hepatorenal syndrome type 1 (HRS-type 1) and evolve to acute tubular necrosis - according to the degree of splanchnic vasodilation/renal hypoperfusion and the reduced cardiac output[4]. HRS type-1 is a prevalently functional disease observed in patients with decompensated cirrhosis, which might remain in a chronic form with less severe renal impairment (HRS-type 2), or progress to acute tubular necrosis[5-7] and exaggerate systemic inflammatory response resulting in multiorgan failure[8]. Recently, patients with cirrhosis who have decreased renal plasma flow with normal or low/normal glomerular filtration rate (GFR) before to develop HRS were defined to be in “Pre-HRS” renal disease[6]. Moreover, the term ‘Hepatorenal Disorders’ has been proposed to group all forms of kidney disease in patients with cirrhosis so as to describe their prognosis and to assist treatment decisions[9]. However, in the majority of patients, HRS type-1 still remains a terminal condition of advanced liver disease requiring coordinated affords in the field of diagnosis, pathophysiology and treatment. In this paper, we are going to address the current knowledge on the evaluation and management of acute and chronic kidney failure presented on patients with cirrhosis. All the suggested directions highlight, to the best extent possible, the bibliographic studies, the expert opinions and recommendations.

BASELINE DIRECTIONS FOR ASSESSMENT OF KIDNEY INJURY IN PATIENTS WITH CIRRHOSIS

The appropriate clinical, biochemical and radiological markers with proven sensitivity for the diagnosis of renal disease in patients with cirrhosis have not been established yet. There are only recommendations for the unique form of kidney injury in patients with cirrhosis, the HRS (Table 1). Renal pathology in patients with cirrhosis includes not only functional abnormalities (developed as a result of changes in hemodynamics, in renal auto-regulation and cardiac dysfunction) but structural abnormalities as well[5].

Table 1 International Ascites Club definition and diagnostic criteria for hepatorenal syndrome[7,116].

1996 criteria
Major criteria
Chronic or acute liver disease with advanced hepatic failure and portal hypertension
Serum creatinine > 1.5 mg/dL or 24-h creatinine clearance of < 40 mL/min
Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses
No sustained improvement in renal function defined as a decrease in serum creatinine to < 1.5 mg/dL or increase in creatinine clearance to 40 mL/min or more following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline
Proteinuria < 500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease
Minor criteria
Urine volume < 500 mL/d	Urine osmolality > plasma osmolality
Urine sodium < 10 mEq/L	Urine red blood cells < 50 per high power field

Physicians caring for patients with cirrhosis should recognize the acute or chronic character of renal disease; the causes of renal injury; the clinical conditions leading concomitantly to acute kidney injury (AKI) and liver dysfunction, and the prognostic factors associated with the progression of AKI. Hypovolemia (due to diuretics, hemorrhage, diarrhoea), acute tubular necrosis, sepsis, nephrotoxic agents (such as nonsteroidal antiinflammatory drugs, aminoglycosides radiological contrasts) and hepatorenal syndrome-type 1 are the most common causes of AKI in cirrhotic patients[4]. It is underlined that type-1 HRS is considered a specific form of AKI[9]. The chronic causes include hepatorenal syndrome-type 2, glomerulonephritis due to hepatitis C virus and hepatitis B virus infection, IgA nephropathy mainly presenting in patients with alcoholic cirrhosis and diabetic nephropathy mainly combined with non alcoholic steatohepatitis[4]. The situations which may worsen the renal and liver function at the same time might be autoimmune diseases, granulomatous diseases, autosomal dominant polycystic kidney disease, shock, pregnancy induced liver disease and drugs (aspirin, NSAIDs and angiotensin converting enzyme inhibitors[4,10,11]. Ultimately, factors associated with the progression of AKI were the hepatic encephalopathy, severe liver and circulatory failure, chronic kidney disease (CKD), low serum sodium concentration and high leukocyte count[12]. This knowledge should be in hand when time for assessment of patients with cirrhosis comes.

In general, differentiation of the main causes of AKI, prerenal “Pre-HRS”, HRS and acute tubular necrosis presents great influence on therapeutic decisions and patients’ prognosis. An easily applicable algorithm proposed by Angeli et al[5], offer great assistance in clarification of the cause of the AKI in patients with cirrhosis. When there is history of dehydration, excessive use of diuretics and bacterial infection on the ground of normal urinary sediment, proteinuria below 0.5 g daily and normal renal ultrasound, the diuretics should be withdrawn and plasma volume expansion should be tried with albumin. If the patient responds to treatment the diagnosis is prerenal. If the patient does not respond, the correct diagnosis is HRS. In case there is recent use of nephrotoxic agents or contrast media and examination shows shock, granular cast in urinary sediment and proteinuria above 0.5 g daily, acute tubular necrosis is the prominent diagnosis. Furthermore, physicians should take into account that one form may convert into another thus HRS may develop on patient with chronic renal disease or evolve in time[4,5].

Moreover, the stage of liver disease will provide considerable hints for the evaluation of kidney injury. At the beginning of cirrhosis splanchnic vasodilatation is masked by increased cardiac output thus glomerulal filtration rate (GFR) is increased[13]. Patients with ascites present severe impairment of renal blood flow[14] and considerable fluctuation of serum creatinine (sCr)[15]. Wide variations may be observed, in regards to volume paracentesis and volume expansion[15]. Patients with advanced liver disease and high bilirubin show overestimation of GFR if evaluation of renal function is based on sCr, since significant interaction may be observed between serum bilirubin and sCr[16,17]. Cirrhotic patients admitted to intensive care unit (ICU) have high mortality rates and may present separate predictors and scoring systems for hospital mortality[18-20]. Emphasis should be given to accurate assessment of renal function in candidates for liver transplantation[21].

The best method for renal function assessment in patients with cirrhosis is the clearance of exogenous markers such as iothalamate, 51Cr-EDTA and inulin[15]. However, its application is limited by the cost and complexity while other equivalent methods for estimating the GFR in patients with cirrhosis have not been established[15]. sCr still remains the key biomarker for the diagnosis of AKI in patients with cirrhosis. Despite all sCr limitations, there have not been detected other widely available and superior serum markers for assessing renal function and predicting outcome in patients with cirrhosis[15]. sCr is still the most practical serum marker for estimation of renal function in cirrhotic patients, it consists the basis of existing definitions of AKI and it is included in the Model for End -Stage Liver Disease (MELD) score {MELD = 3.8 [Ln serum bilirubin (mg/dL)] + 11.2 (Ln INR) + 9.6 [Ln serum creatinine (mg/dL)] + 6.4}, which is used to allocate patients for liver transplantation[22]. Nevertheless, sCr should be interpreted with caution, since there is no universal standardized creatinine assay; there are interlaboratory variations, interactions with bilirubin and great influence by numerous non-renal factors such as body weight, race, age, gender[23-25]. Moreover, sCr within the normal ranges does not exclude significant renal impairment in patients with cirrhosis[26] as it overestimates renal function due to decreased creatine production by liver malnutrition and muscle wasting[27].

RECENT KNOWLEDGE ON EVALUATION OF RENAL DYSFUNCTION IN PATIENTS WITH CIRRHOSIS

So far, the most widely used criterion for the diagnosis of acute renal failure in patients with cirrhosis is the sCr level ≥ 1.5 mg/dL (133 μmol/L) (conventional criteria). A propose for the improvement on the current classification of acute renal dysfunction in cirrhosis is the diagnostic criteria developed by the Acute Kidney Injury Network (AKIN)[28] (Table 2). This is a consensus definition for acute kidney injury (AKI), a new term for acute renal failure, in order to be identified earlier patients with worse prognosis. According to AKIN criteria, AKI is defined as an increase in sCr level ≥ 0.3 mg/dL (≥ 26.4 μmol/L) or ≥ 150% (1.5 fold from baseline) within 48 h from the first measurement or a urine output of less than 0.5 mL/kg per hour for more than 6 h[28-30] and is divided in three stages. AKIN criteria in cirrhotic patients have been validated with six prospective clinical trials[8,12,20,31-33]. The patient population in the five studies included hospitalized cirrhotic patients with or without ascites[8,12,31-33], while in one study patients with cirrhosis were admitted in ICU[20]. All studies concluded that AKIN criteria accurately predicted in- hospital mortality, length of hospital stay and organ failure. However, when AKIN criteria compared to conventional criteria, they were not found to be superior[33]. The authors of this study noted that the addition of either the progression of AKIN stage or the cut off sCr ≥ 1.5 mg/dL to the AKIN improved their prognostic accuracy[33]. A step forward in this evaluation was made by Fagundes et al[12] who proposed modified cirrhosis-AKI classification and validated it in 375 consecutive patients hospitalized for complications of cirrhosis. Patients with cirrhosis were categorized into three groups: (1) patients with AKI stage 1 and peak of sCr ≤ 1.5 mg/dL; (2) Patients with AKI stage 1 and peak of sCr > 1.5 mg/dL; and (3) patients with AKI stage 2 or 3. By applying this modified classification a better risk stratification for patients with cirrhosis was achieved considering also the cause of AKI.

Table 2 Acute kidney injury network and risk, injury, failure, loss, and end stage criteria for the diagnosis of acute kidney injury[117].

AKIN criteria	Urine output	RIFLE criteria
Serum creatinine	(common to both AKIN and RIFLE)	Class	Serum creatinine or GFR
Stage 1
Increase of more than or equal to 0.3 mg/dL (≥ 26.5 μmol/L) or increase to more than or equal to 150% to 199% (1.5- to 1.9-fold) from baseline	Less than 0.5 mL/kg per hour for more than 6 h	Risk	Increase in serum creatinine × 1.5 or GFR decrease > 25%
Stage 2
Increased to more than 200% to 300% (≥ 2- to 2.9-fold) from baseline	Less than 0.5 mL/kg per hour for more than 12 h	Injury	Serum creatinine × 2 or GFR decreased > 50%
Stage 3
Increased to more than 300% (≥ 3-fold) from baseline, or more than or equal to 4.0 mg/dL (≥ 354 μmol/L) with an acute increase of at least 0.5 mg/dL (44 μmol/L) or on RRT	Less than 0.3 mL/kg per hour for 24 h or anuria for 12 h	Failure	Serum creatinine × 3, or serum creatinine > 4 mg/dL (> 354 μmol/L) with an acute rise > 0.5 mg/dL (> 44 μmol/L) or GFR decreased > 75%
		Loss	Persistent acute renal failure = complete loss of kidney function > 4 wk
		End-stage kidney disease	ESRD > 3 mo

For conversion of creatinine expressed in SI units to mg/dl, divide by 88.4. For both AKIN stage and RIFLE criteria, only one criterion (creatinine rise or urine output decline) needs to be fulfilled. Class is based on the worst of either GFR or urine output criteria. GFR decrease is calculated from the increase in serum creatinine above baseline. For AKIN, the increase in creatinine must occur in < 48 h. For RIFLE, AKI should be both abrupt (within 1–7 d) and sustained (more than 24 h). AKI: Acute kidney injury; AKIN: Acute Kidney Injury Network; ESRD: End-stage renal disease; GFR: Glomerular filtration rate; RIFLE: Risk, injury, failure, loss, and end stage; RRT: Renal replacement therapy.

Serum Cystatin C (CysC) is another marker for evaluation of acute renal dysfunction preferably in female patients with progressive cirrhosis[34]. It has been shown that in this cirrhotic population (women with cirrhosis Child - Pugh score C)[34]. CysC presented high diagnostic sensitivity, greater than sCr in detection of acute renal impairment[34,35]. Indeed it was proved that CysC correlated with the severity of liver fibrosis and with the GFR better than sCr[35-37], but this has not been confirmed in other studies[38].

Promising information for acute kidney dysfunction in cirrhotic could be also derived from urine. A novel kidney biomarker associated with early detection of acute tubular injury is neutrophil gelatinase -associated lipocalin (NGAL) measured in blood and in urine. Many studies in several clinical situations[39-41] have underlined that the NGAL increased two hours after the induction of AKI, before of the sCr elevation. In cirrhotic patients, preliminary studies have reported that NGAL levels were higher in those with HRS[42] compared to those without renal disease; NGAL was associated with the prediction of short-term mortality[43,44] and it could be used for differentiation of prerenal azotemia, acute tubular necrosis and HRS[45]. Urinary NGAL has been found to be 20 ng/mL in healthy population and in prerenal azotemia, 105 ng/mL in HRS, 325 ng/mL in AKI and 50 ng/mL in CKD[44]. Furthermore, another powerful tool in renal disease detection could be the ratio of urinary sodium to potassium. If that ratio in a random urine sample of patients with decompensated cirrhosis and ascites is less than 1 the diagnosis of renal dysfunction (GFR < 60 mL/min) is possible[46]. Nevertheless all these findings require confirmation in additional studies.

Ultimately, encouraging method for early acute detection of renal hemodynamic disturbances of patients with cirrhosis showed the measurement of renal resistive index (RI) by renal duplex doppler ultrasound. In general, a RI more the 0.7 is indicative of renal failure, confirming high blood velocity waveform of renal artery and high peripheral arterial resistance[47]. In patients with cirrhosis RI over 0.7 has been predictor of renal dysfunction and HRS[48,49] and it has correlated significantly with MELD score, MELD-Na score, sCr and hyponatriemia as well[50]. In addition, it might demonstrate the progress of renal disease since it reached its highest levels in patients with refractory ascites compared with patients with compensated cirrhosis and those with diuretic responsive ascites[48]. Future research is needed to elucidate RI role in this patient population.

In regards to the evaluation of CKD, the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines have been suggested[9]. According to KDOQI[51], CKD is defined as a GFR of less than 60 mL/min for more than three months, calculated using the modified diet in renal disease (MDRD)-6 formula (Appendix 4) supporting its potential usefulness in the decision making for simultaneous liver and kidney transplantation. This hypothesis has been tested in patients with stable cirrhosis in the study of Francoz et al[52]. They showed that MDRD-6 formula was superior to MDRD-4 and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas identifying stable cirrhotic patients with markedly impaired renal function, including those with ascites (Table 3). However, MDRD-6 formula underestimated renal function in patients with GFR more than 30 mL/min subjecting them to possible unnecessary combined kidney and liver transplantation. Recently, CKD-EPI Cys C-Cr equation was shown to be the most accurate GFR-estimating formula compared to sCr or CysC-based formulas in cirrhosis. This formula was proposed to evaluate non AKI in cirrhosis until a brand, radical and specific for this population equation is discovered[53].

Table 3 Formulas for estimating the glomerular filtration rate: modified diet in renal disease-4, modified diet in renal disease-6, chronic kidney disease epidemiology collaboration (mL/min per 1.73 m²)[118-120].

MDRD-4 formula (1)	186 × [creatinine (mg/dL)] -1.154 × [age (yr)] 0.203 × (0.742 if patient is female) × (1.21 if patient is black)
MDRD-6 formula (2)	170 × sCr (mg/dL)-0.999 × age-0.176 × 1.180 (if black) × 0.762 (if female) × serum urea nitrogen-0.170 × albumin 0.138
CKD-EPI equation (3)	141 × min (sCr/κ, 1)α× max (sCr/κ, 1)-1.209 × 0.993 Age × 1.018 (if female) × 1.159 (if black)

MDRD: Modified diet in renal disease; CKD-EPI: Chronic kidney disease epidemiology collaboration.

Accurate evaluation of renal function in cirrhotic patients, who are candidates for liver transplantation (LT) is crucial. Kidney disease is the key factor for determination of transplant status and highly affects the choice of simultaneous kidney and renal transplantation, the initial immunosuppression and the survival of these patients[54-56]. GFR, sCr and serum sodium have been recognized as independent predictors of mortality in patients with decompensated cirrhosis[57,58]. In this case estimation of GFR should be made accurately by exogenous filtration markers. Particularly for patients with established HRS, a modification of MELD calculation has been proposed, to obtain patients with HRS the right priority in the waiting list, concerning that therapy can reduce their baseline MELD score[59]. According to this modification, the baseline MELD score before starting therapy should be used in patients with HRS who have been stabilized with therapy; the MELD score considering the pharmacological treatment as dialysis should be applied in patients with continuous recurrence of HRS and the highest MELD-Na over time should be received in patients with repeated recurrence of HRS type-2. Renal biopsy is advisable if GFR is between 30-60 mL/min and there are signs of parenchymal renal disease -hematuria (more the 50 red cells per high power field), proteinuria > 0.5 g/daily-and chronic renal abnormalities on the ground of comorbidities such as diabetes mellitus, hypertension and viral infection[15]. The detection of potential reversible renal disease and vascular lesions- hazardous for calcineurin-inhibitors nephrotoxicity- may be of value for the management before and after transplantation.

Kidney failure at admission or during ICU stay is a crude predictor of mortality in critically ill patients with cirrhosis. Despite supportive treatment measures, mortality was high and the risk for death was multiplied with the increasing severity of the kidney disease[1,60]. In this patient population, RIFLE classification presents the best predictive ability for ICU and hospital mortality[18,19]. The RIFLE denomination is an acronym which refers to risk (risk of renal dysfunction); injury (injury or damage to the kidney); failure (renal failure); loss (loss of kidney function); end (end stage renal disease) (Table 2). It was entered by Acute Dialysis Quality Initiative (ADQI) as an attempt to standardize the definition of acute renal failure and to describe the severity of AKI[61]. It allows the evaluation of the progression of renal injury as AKI is a dynamic process[62]. However, RIFLE score lack of a uniform approach in a patient population presenting with multiorgan failure, since it is focused only on kidney pathology. In keeping with this, a new score (MBRS) has been introduced combining four parameters: mean arterial pressure, bilirubin, respiratory failure and sepsis displayed an excellent area under the receiver operating characteristic curve (0.898 ± 0.031) for prognosis of mortality. This tool has been applied in a total of 301 critically ill cirrhotic patients[63,64] and proved that is an accurate, handy, user- friendly and low -cost scoring system. If it is above 2, cirrhotic patients should be prioritized for LT[64].

Overall, when it comes to evaluate renal function in patients with cirrhosis determination of AKI, CKD or AKI on CKD should be made. HRS diagnosis is the first which should be excluded by the algorithm of Angeli et al[5]. The acute renal function is proposed to be assessed with modified AKIN and the baseline renal function in stable patients with MDRD-6 formula or CKD-EPI Cys C-Cr equation. MBRS score or RIFLE criteria for AKI evaluation should be tried in critically ill cirrhotic patients, while in candidates for transplantation, GFR should be preferably measured with exogenous markers for accurate assessment of renal function. Serial plasma measurements with delayed sampling to allow equilibrium between plasma and intracellular space, especially ascitic fluid would give a more precise GFR[65]. All cirrhotic patients should undergo renal ultrasound for measurement of RI, in every stage of liver dysfunction and urine microscopy for differentiation of all causes of AKI. Renal biopsy should be performed when GFR is between 30-60 mL/min and there are signs of parenchymal renal disease (Table 4).

Table 4 Recomendations for renal function evaluation in subgroups of patients with cirrhosis.

Differentiate prerenal kidney disease, hepatorenal syndrome and acute tubular necrosis	Angeli et al[5] algorithm
Acute kidney injury	Modified cirrhosis–acute kidney injury classification sCr increase ≥ 0.3 mg/dL (≥ 26.4 μmol/L) or more than 150% (1.5 fold from baseline) within 48 h from the first measurement[12]
Chronic kidney disease	KDOQI[49] guidelines Glomerular filtration rate below 60 mL/min for more than three months, calculated using the modified diet in renal disease-6 formula chronic kidney disease epidemiology collaboration Cys C-Cr equation[51]
Critically ill cirrhotic patients	RIFLE score[18,19] MBRS score[61,62] combining mean arterial pressure, bilirubin, respiratory failure and sepsis
Candidates for liver transplantation	Exogenous filtration markers If there is suspicion for parenchymal disease and Glomerular filtration rate is between 30-60 mL/min consider renal biopsy
Advanced cirrhosis	Cystatin C
Difficulties in differentiation of acute tubular necrosis	NGAL
All patients with cirrhosis in every stage of liver disease	Renal resistive index estimation by renal duplex doppler ultrasound

KDOQI: Kidney disease outcomes quality initiative.

INACCURACIES OF RENAL ASSESSMENT STRATEGIES IN PATIENTS WITH CIRRHOSIS

Regarding the AKIN criteria, the urine volume cannot be applied in patients with cirrhosis since it may be markedly biased. Errors in the timing and the complete of urine collection are very common. Moreover, AKIN overestimate mortality, because they detect earlier patients with worse prognosis[32]. Since sCr cannot be removed from clinical practice, physicians should use it with caution in patients with advanced cirrhosis. The inadequacies of sCr are more pronounced in this patient group, due to high bilirubin and refractory ascites. The establishment of creatinine levels with enzymatic assays partially overcame this problem, but there are more expensive[66]. Similarly, none of the creatinine -based mathematical equations are precise acute markers for renal function evaluation in cirrhosis[67]. The body weight cannot be accurately estimated on the ground of ascites and edema, and there is disproportional high creatinine secretion from the tubules in regards to the level of creatinine filtered by the glomerulus[23]. Similarly, evidence has not clarified whether sCysC offers clear advantage comparing to sCr in all cirrhotic patients, neither improve the predictive power of MELD score[68]. sCysC may also be influenced by body composition, abnormal thyroid function, systemic inflammation and corticosteroid use, while its assay although easy applicable is of high cost[41]. In parallel substitution of sCr by sCysC did not improve the prognositic ability of MELD-score and creatinine -based equations[38,68]. Estimating GFR with the gold standard measures is the method of choice, but in every day routine is expensive, time-consuming, radioactivity transmitter and fatiguing[21]. Ultimately, renal biopsy is not easily applicable to patients with cirrhosis. Coagulation disorders are common in cirrhotic and the prolonged INR predispose to high risk of hemorrhages. In this situation, transjugular route is preferable than the percutaneous route, since it has been proved equivalent efficient[69]. Contraindications for biopsy are small size kidneys, large volume ascites and poor cortical differentiation[15].

MANAGEMENT OF RENAL FUNCTION IN PATIENTS WITH CIRRHOSIS

Research has made an enormous progress by finding treatment directions for HRS, which was previously fatal within a few days or weeks. However, no guidelines have been established for the treatment of patients with cirrhosis and kidney disease. Management options should be based on expert recommendations[9], proposed algorithms[33] and knowledge of the nature of renal disease[6,8]. It is essential to recognize early AKI - mainly diagnosis of HRS, which should be detected within 48 h, following the currently accepted guidelines[10,59] (Table 1) - to determine the chronic damage of the kidneys and to take the best measures for improving hepatic function. Patients with renal disease due to HRS, have much worse prognosis compared to patients with parenchymal renal disease[59]. Amelioration of the underlined liver disease is very impressive in patients with alcoholic liver disease after recovery from alcoholic hepatitis, therapy with baclofen[70] and in patients with decompensated cirrhosis due to hepatitis B virus infection after receiving antiviral therapy[71-73]. The choice of therapy depend upon the experience of the medical centre, the availability of certain drugs, the unit in which patient is admitted (ICU or not ICU) and whether the patient is a candidate for LV.

First line treatment

First line treatment should aim at the elimination of the potential pathophysiological factors resulting on HRS. Hemodynamic monitoring and management of fluid balance is essential for preventing the relative renal hypoperfusion, maintaining effective circulatory volume and renal perfusion pressure. Traditional measures of intravascular volume evaluation such as right atrial and pulmonary artery pressures are not considered inadequate for this patient group, so continuous central venous pressures and serial indirect or/and direct measurements of cardiac indices are preferable[9]. The current classification systems are helpful in early recognition of AKI indices and therefore withdrawing the potential causes of renal injury. Patients with AKIN stage 1 and sCr ≥ 1.5 or initial AKIN stage > 1 should be at close monitoring and receive therapeutic measures for maximum two days[33]. These involve nephrotoxic medications-antibiotics and analgetics-, gastrointestinal bleeding and diuretics, which exacerbate hypovolemia and trigger sympathetic and renin-angiotensin-aldosterone system (RAAS). High level of suspicion is needed regarding the spontaneous bacterial peritonitis since infections very common trigger HRS. Moreover, albumin infusions will correct hypoalbuminemia and partial ascites evacuation will alleviate circulation[33,74]. In the setting of alcohol-related cirrhosis and ascites, the intestinal decontamination with rifaximin may also improve systemic hemodynamics and renal function[75]. If the clinical condition of congested patients (the groups previously mentioned) does not improve within two days, differential diagnosis with HRS should be done and other specific regimens are required[5] (Table 5).

Table 5 Recomendations for management of patients with cirrhosis.

First line therapy
Recognize and withdraw all causes of acute kidney disease
Resolve primary liver disease
Encounter hypoalbuminemia with albumin infusion and tension ascites with repeated paracentesis plus albumin
Have a high level of suspicion and treat spontaneous bacterial peritonitis
Be vigilant and have into close monitoring patients win acute kidney injury network stage 1 and sCr > 1.5 mg/dL (133 μmol/L) or initial acute kidney injury network stage > 1
If there is no improvement within 2 d, proceed to specific treatment measures
Second line therapy
Patients hospitalized at the ward	If the diagnosis of hepatorenal syndrome has been placed:
	Give albumin and terlipressin in continuous infusion
	If there is improvement within 4 d continue with oral midrodrine
	When terlipressin is unavailable:
	Give midrodrine plus octreotide plus albumin
Patients admitted to intensive care unit	Norepinephrine plus albumin
Third line therapy
Patients who qualify for transplant	Consider liver or simultaneous liver kidney transplantation
	Give therapeutic bridges – Dialysis, transjugular intrahepatic portosystemic shunt
Patients who do not qualify for transplant	Continue the combination of terlipressin plus albumin
	Dialysis, TIPS

Second line treatment

Second line therapy encompasses measures undertaken after posing the diagnosis of HRS. The supportive measures are directed mainly into portal hypertension and arterial vasodilatation reversal. Albumin effusion combined with vasoconstrictors is the basic therapy for effective management of hypovolemia[5,9]. The main effect of albumin is the oncotic pressure increase resulting in volume expansion. However, albumin shows additional effects which make it extremely beneficial for patients with HRS. It shows metabolic, immune and vasoconstrictor effects, through binding of endotoxin, nitric oxide, bilirubin, bile acid and fatty acids[76,77] and improves cardiac output, through improvement of cardiac contractility, cardiac preload and volume expansion[78,79]. On the other side, terlipressin is an agonist of renal vasopressin V2 receptors, which reduce splachnic vasodilatation, increase the MAP and reduce the nitric oxide synthesis during sepsis[80]. The combination of them leads to renal function normalization in 34%-65% of cases[81,82], expends the number of patients undergoing LT[83], additionally improving their outcome[84] and it increases short -term survival by 34%-43%[82,85,86]; while it is hypothesized that ameliorates also tubular damage[5]. They have been applied in a special protocol which has shown efficacy in 59% of cases[87] and its discontinuation has been followed by HRS recurrence in 15%-22%[82,85,86,88-91]. The protocol has been proposed to be administered until there are signs of improvement, but not more than two weeks. The decrease of sCr <1.5 mg/dL (133 μmol/L) or the decrease of sCr > 50% but ≥ 1.5 mg/dL (133 μmol/L), the decrease of bilirubin < 10mg/dL and the elevation of MAP ≥ 5 mmHg at day 3 of treatment are the predictors of response[87,92,93]. If patient respond, some centers continue therapy with midodrine (an oral α1-adrenergic agonist with vasoconstrictive properties) indefinitely to keep higher MAP and to compensate refractory ascites[94]. If there is no improvement in renal function after two weeks, the protocol maybe repeated -there have been reports for protocol administration up to eight months[9,74,95,96] - or other interventional options are applied regarding the patient status and the available treatment options of the centre. Moreover, changes on terlipressin administration modality (given as continuous infusion instead of iv pulses) accounted for enhancement of its efficacy[5,97] (Table 6).

Table 6 Scheme for terlipressin and albumin administration[5,97].

Terlipressin is given as an intravenous bolus 1 to 2 mg every four to six hours

Albumin is given for two days as an intravenous bolus 1 g/kg per day (100 g maximum) followed by 25 to 50 g /d until terlipressin therapy is discontinued

In some cases terlipressin is not applicable. These are when there are contraindications of its use, when there is not available and when the patient is admitted on ICU. In general, the contraindications of terlipressin use are ischemic cardiovascular disease, heart failure, arrhythmias, asthma, respiratory failure and heavy hyponatriemia[4]. Terlipressin use is limited in some countries because of its high cost and the lack of randomized trials proving superiority of terlipressin in comparison to other vasoconstrictors. When patients are admitted to ICU they usually treated with terlipressin[76,98-100] in patients being in ICU and because the cost of norepinephrine therapy is three times less than the cost of terlipressin[100]. Norepinephrine is difficult to be administered in the ward since it requires continuous intravenous infusion and hemodynamic monitoring, so instead of terlipressin, other vasoconstrictors maybe used in combination with albumin. These are octreotide, a synthetic analog of somatostatin and midodrine. However, the effect of octreotide, either used alone or with albumin, does not appear to be beneficial for renal function improvement[99,101] and midodrine alone or in combination with albumin has not been evaluated in patients with HRS type -1. Only when octreotide was used in conjunction with midodrine and albumin has normalized renal function in 49%[77,102,103], has increased MAP[77] and survival[102].

Third line treatment

When pharmacological measures are insufficient, transplantation is the treatment of choice[8]. MELD score permits selection of patients needing liver transplant, while patients who are risk for not -recovery of renal function simultaneous kidney and liver transplant is required[9]. In the direction of combined liver and kidney transplantation leads the duration of HRS (more than four weeks), AKI on CKD, and baseline diseases (such as hypertension, diabetes and obesity) which predispose to kidney disease progression (Table 7). If the patient meets the requirements to be listed for transplant, dialysis and transjugular intrahepatic portosystemic shunt (TIPS) are the bridging therapies to keep the transplant candidate in the best clinical status. It is essential to resolve HRS since is associated with many perioperative complications and decreases patient survival.

Table 7 Published guidelines on selection criteria for simultaneous liver-kidney transplantation.

Davis et al[121], 2007

Patients with CKD with CrCl (preferentially iothalamate) of ≤ 30 mL/min for > 3 mo

Patients with AKI and/or HRS on dialysis for ≥ 6 wk

Patients with prolonged AKI with kidney biopsy showing fixed renal damage

SLK was not recommended in patients with AKI not requiring dialysis

Eason et al[122], 2008

Patients with CKD with GFR ≤ 30 mL/min > 3 mo

Patients with AKI/HRS with sCr ≥ 2 mg/dL and on dialysis ≥ 8 wk

Patients with evidence of CKD and kidney biopsy with > 30% GS or 30% fibrosis

Other criteria that was recommended to be considered: Presence of co-morbidities: Diabetes, Hypertension, age > 65 yr, renal size and duration of sCr > 2 mg/dL

Nadim et al[123], 2012

Persistent AKI ≥ 4 wk with one of the following:

Increase Scr ≥ 3-fold from baseline or on dialysis

GFR ≤ 35 mL/min (MDRD-6) or ≤ 25 mL/min (iothalamate)

CKD ≥ 3 mo with one of the following:

eGFR ≤ 40 mL/min (MDRD-6) or ≤ 30 mL/min (iothalamate)

Proteinuria ≥ 2 g/d

Kidney biopsy showing > 30% GS or > 30% interstitial fibrosis

Note: Higher GFR threshold with MDRD-6 was to account for the approximate 30%- 40% overestimation that has been described when compared to iothalamate.

CKD: Chronic kidney disease; CrCl: Creatinine clearance; HRS: Hepatorenal syndrome; AKI: Acute kidney injury; SLK: Simultaneous Liver-Kidney; sCr: Serum creatinine; GFR: Glomerular filtration rate; GS: Glomerulosclerosis; MDRD-6: Modification of diet in renal disease formula calculated using six variables of serum creatinine, serum urea, serum albumin, age, gender.

In general, dialysis procedures have not improved the long -term survival in patients with HRS and they have been associated with high risk of blood pressure decline, hypothermia, bradycardia, tissue hypoxia and clotting[4]. That is why they are applied under special situations, when there are indications for reversibility of AKI, hyperkalemia, hypervolemia not responding to diuretics, severe metabolic acidosis, acute on chronic liver failure and fulminant liver failure[9,104,105]. The choice of modality [continuous renal replacement therapy, intermittent hemodialysis, Molecular Adsorbent Recirculating System (MARS)] depends on the abilities and the experience of the centre, while non standard anticoagulation measures are indicated. Schemes with saline flushing, minimal dose of heparin or minimal dose of citrates are preferable. Peritoneal dialysis may be another option to remove ascites and resolve cirrhosis complications, such as encephalopathy, without exposing patient to anticoagulation and to other dialysis complications[106,107].

TIPS is an intervention that enhances the return of blood in the right heart and resolve the reduced sympathetic and RAAS activity in HRS type II, suggesting an improvement in systematic hemodynamics[108-110]. It is indicated in cirrhotic patients with refractory ascites requiring repeated paracentesis[109-112] because it has conferred positive impact on ascites and renal function amelioration. Nevertheless, it has not improved significantly mortality[113]. Furthermore, renal function improvement does not come fast, it comes after weeks or months[114], so very ill patients, without significant liver function reserve (INR > 2, bilirubin> 5 mg/dL or Child Plugh > 11), hepatic encephalopathy and cardiopulmonary disease[9] should not undergo it. Complications of TIPS procedure are high rates of encephalopathy, liver insufficiency, cardiac failure, infection of the stent and hemolysis[111,115]. In patients with HRS 1, preliminary studies[108,111] about TIPS showed improvement of renal function in parallel with survival, but it cannot be applied in clinical practice yet as a main treatment. At present, TIPS can be used in selected patients without severe liver dysfunction as a bridge for LT or in patients with stabilized liver function not enlisted, as a long term -therapy[74] (Table 5).

CONCLUSION

Patients with cirrhosis and renal failure are high-risk patients who can hardly be grouped to form precise instructions for diagnosis and treatment. AKI is a portentous manifestation of circulatory dysfunction on patients with cirrhosis, which has a detrimental impact on their recovery and survival. Close surveillance, well -classified definitions and scoring systems (AKIN, RIFLE) aim in early recognition of renal disease. Attempts are made to correlate non invasive biomarkers of kidney damage and kidney function (NGAL, sCysC) to pathological findings. Studies on better using pharmacological and interventional measures are underway promising better and quick recovery. Physicians should be updated on new therapeutic modalities, proposed recommendations and algorithms in order to translate them into clinical practice.