Renal Dysfunction in Hepatic Failure


GFR criteria

Urine output criteria



SCr increased ×1.5

GFR decreased >25 %

<0.5 mL/kg/h for >6 h

High sensitivity (risk > injury > failure)


SCr increased ×2

GFR decreased >50 %

<0.5 mL/kg/h for >12 h


SCr increased ×3

GFR decreased 75 %

SCr ≥4 mg/dL

>0.3 mL/kg/h ×24 Oliguria

Anuria × 12 h


Complete loss of renal function >4 weeks
High specificity


Complete loss of renal function >12 weeks

Table 34.2
The proposed diagnostic criteria for AKI in cirrhosis



Acute kidney injury

Rise in Scr of ≥50 % from baseline or by ≥0.3 mg/dL in <48 h. HRS-1 is a specific form of AKI

Chronic kidney disease

GFR of <60 mL/min for >3 months calculated using MDRD6 formula. HRS-2 is a specific form of CKD

Acute-on-chronic kidney disease

Rise in SCr ≥50 % from the baseline or rise in SCr ≥0.3 mg/dL in <48 h in patients with cirrhosis with GFR <60 mL/min for >3 months calculated using MDRD6 formula

The AKIN definition included an absolute increase in SCr of ≥0.3 mg/dL within 48 h or 50 % increase of SCr from the baseline value within 24 h and that is irrespective to the etiology of the AKI. This definition of AKI will cover a wide spectrum of renal diseases in patients with acute or chronic hepatic failure. Accordingly, the presence of chronic renal failure will be defined as continuous renal impairment beyond the 3-month cutoff period. However, patients with ESLD and with the application of either these two definitions will result in fewer cases to be qualified to have the HRS-1 and the rest will fall within the definition scope of AKI. Accordingly, the ADQI proposed to use the terminology of hepatorenal disorders to define all types of AKI that accompanied ESLD and leaving the HRS-1 to be considered in small percentage of patients when they meet certain diagnostic criteria [5]. CKD is defined when the GFR dropped below a cutoff limit of 60 mL/min/1.73 m2 for more than 3 months. In patients with ESLD there is difficulty to accurately measure the GFR due to the fact that most of the equations that are used to calculate the GFR are relayed on the SCr which is not a sensitive marker for renal function especially in ESLD [6]. The most widely used formula to calculate the GFR in patients with ESLD is the abbreviated modification of diet in renal disease (aMDRD) in which eGFR is equal to 186 × (SCre mg/dL) − 1.154 × age − 0.203 × 0.742 if patient is female ×1.21 if patient is African-American [7]. By using this formula and with the applying of definition of CKD, it is acceptable to consider HRS-2 as CKD when the GFR is <60/mL/min which is corresponding to SCr of 1.5 mg/dL. Acute deterioration of renal function in patients with baseline CKD or HRS-2 (acute on chronic) is still defined by the percentage changes of SCr from the baseline.

Hepatorenal Connections

The pathophysiological changes in cirrhosis are mostly associated with systemic vasodilatation and splanchnic hyperemia which is accompanied by reflex stimulation of the sympathetic system to maintain hemodynamic stability [8, 9]. As a result there is an increase in the circulating catecholamine and activation of the renin-angiotensin system (RAS) . The role of renal sympathetic nervous system stimulation in the etiology of intrarenal vasoconstriction is at best a contributing factor since renal sympathetic denervation did not reverse the vasoconstrictor response that was demonstrated in HRS [10].

The activation of RAS may play a serious role in the etiology of intrarenal vasoconstriction and eventful renal damage as well as in the propagation of hepatic fibrosis with further deterioration of hepatic function [11, 12]. Recent studies indicated that angiotensin II can activate the contraction of the hepatic stellate cells which results in increased intrahepatic resistance to portal blood flow with the development of portal hypertension. The clinical values of ACE inhibitors and/or angiotensin receptor blockers (ARB) in cirrhotic patients are still required to be evaluated since the results of recent clinical trials are not very promising [13, 14]. The issues related to the use of ARBs and ACE inhibitors in cirrhotic patients are related to the development of systemic hypotension which can further compromise renal perfusion and blood flow. A new scientific discovery of the presence of a homolog of ACE that is present in the heart, kidneys, and testis which can convert angiotensin II into angiotensin (1–7 and 1–9) both can oppose the effects of the parent agent on the vascular resistance and on the hepatic cells. The clinical applications of these agents may pave the way for new therapeutic interventions to prevent renal injury in liver cirrhosis [15].

The presence of cirrhotic cardiomyopathy in patients with ESLD is a well-documented phenomena which can be detected in all kinds of cirrhosis not only in alcohol-induced cirrhosis. The severity of cardiac involvement is clearly related to the severity of liver disease and it tends to improve within 6–12 months after successful liver transplantation [16]. The cardiac dysfunction can be partially explained by high plasma levels of brain natriuretic peptide in the presence of relative hypovolemia or low preload (due to vasodilatation) and it correlates very well with the severity of liver disease [17].

The contribution of high levels of circulating catecholamine in the etiology of cardiomyopathy in ESLD is undeniable and can lead to myocardial growth and myocardial fibrosis with impairment of myocardial relaxation. The hyperactivity of sympathetic system can result in beta-adrenergic receptor down-regulation and abnormality of the signal transduction with overall reduction in the response to sympathomimetic agents [18]. Recently, endogenous cannabinoids (EC) which are lipid-signaling molecules have been recently found to be upregulated in liver disease and considered to be a factor not only in pathogenesis of liver cirrhosis but also in cirrhosis-induced hyperdynamic circulation and/or cirrhotic cardiomyopathy [19].

In ESLD there is breakdown of intestinal mucosal barrier which results in translocation of bacteria and endotoxin from the intestinal tract to the systemic circulation by passing the hepatic filter through the porta-systemic shunting or due to impairment of hepatic de-toxification function. The presence of chronic low levels of endotoxemia in patients with ESLD is the underlying mechanism of the chronic inflammatory response and the resultant splanchnic and systemic vasodilatation [20]. The increased production of pro-inflammatory cytokines (TNF-α, IL-18) which is coupled with excessive production of nitric oxide (NO) can further impair the cardiac dysfunction. The contribution of cardiomyopathy to the pathogenesis of AKI and especially to HRS is still controversial, but cirrhotic patients demonstrate that an inability to increase cardiac output during stress (sepsis, surgery) may further impede the already compromised renal blood flow and lead to AKI. The presence of excessive vasoactive mediators in ESLD can lead directly or indirectly through activation of secondary mediators to low SVR and high intrarenal vascular resistance. These agents include endotoxin, NO, TNF-α, IL-18, endothelin, glucagon, and prostaglandins. The increased production of NO is due to up-regulation of the inducible nitric oxide synthase (iNOS) , possibly induced by high shear stress on the vascular beds of both systemic and splanchnic and the presence of access of endotoxin. The high levels of NO are not only related to increased production but also decreased NO removal. In a recent study by Serna et al. [21] the investigators demonstrated the presence of high dimethylarginine dimethylaminohydrolases (DDAHs) which indicates an increased breakdown of asymmetric dimethylarginine (ADMA) , the natural NOS inhibitor which results in further increased NO production with sustained mesenteric vasodilatation. A new theory is emerging to explain in the intrarenal vasospasm while there is widespread systemic and splanchnic vasodilatation, in which ADMA plays the pivotal role in the inhibition of intrarenal NO production resulting in the vasoconstriction [22, 23].

Other known mediators of the intrarenal vasodilatory response are PGs, which are normally increased whenever there is intrarenal vasoconstriction as demonstrated by increase in urinary excretion of these PGs, except in patients with HRS [24]. The finding that there is a low level of vasodilatory PGs prompted the administration of these agents to patients with HRS; however, the results are still disappointing and may be due to further deterioration in the SVR and decrease in renal perfusion pressure or simply they play minor role in the pathophysiology of AKI of ESLD.

The Spectrum of AKI in ESLD

The most common AKI in patients with ESLD is acute tubular necrosis (ATN) 35 % and prerenal azotemia 32 %, HRS-1 20 %, and HRS-2 6.6 % and the rest are miscellaneous causes.

Prerenal Azotemia

It is defined as functional derangement of kidneys that can be caused by an array of causes which operate or start outside the kidneys. The most common etiology is preload reduction due to hypovolemic and hemorrhagic shock. Another etiology is related to low cardiac output that can be caused by multiple factors such as cardiogenic shock, septic shock, and hypovolemic shock. Prerenal azotemia is a common etiology for AKI in ESLD and caused mostly by relative hypovolemia (induced by low SVR), paracentesis and aggressive diuretic therapy, low cardiac output due to cirrhotic cardiomyopathy, and sepsis. Once the prerenal azotemia is set in and if not treated appropriately it can lead to intrinsic renal injury and can set the motion for ATN or HRS.

Acute Tubular Necrosis

The etiology of acute tubular necrosis (ATN) in patients of ESLD is mostly related to preload reduction as in hemorrhagic shock, hypovolemic conditions mostly due to aggressive diuretic therapy, septic shock (bacterial peritonitis), and use of nephrotoxic agents. The differentiation between ATN and HRS-1 is difficult to establish due to overlap in presentation and in the precipitating factors. HRS-1 mostly responds to preload optimization and/or vasoactive agents with the removal of the precipitating factors (sepsis, diuretics, nephrotoxic drugs) or by liver transplantation [25, 26]. However in ATN there are many pathological and structural damages within the renal tubules that are attributed to ischemia and will require long time for regeneration and repair process (average 1–3 weeks).

Analysis of urine can be helpful in the differential diagnosis such as urine osmolality which is high in HRS-1, urine sodium which is high in ATN, and the presence of cellular casts, hemoglobin, and myoglobin are mostly associated with ATN. Doppler ultrasound can be used to confirm the presence of intrarenal vasoconstriction which is the hallmark of HRS and can exclude other etiologies for the AKI [26]. Recently, the role of certain urinary biomarkers in the differential diagnosis of HRS-1 and ATN started to emerge as specific and accurate diagnostic tests. Although still not commonly used in clinical practice but the possibility for future use is there, such biomarkers include kidney-injury molecule-1 (KIM-1), interleukin-18 (ILT-18), and neutrophil-gelatinase-associated-lipocalin (NGAL) [27].

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is defined as reversible renal functional derangement in patients with ESLD. The diagnosis is usually established by the exclusion of other causes for renal impairment and failure to respond to volume resuscitation. Certain diagnostic criteria were established by International Ascites Club (IAC) in 2007 to confirm the diagnosis of HRS and to differentiate from other causes of AKI in ESLD (Table 34.3) [1, 28]. HRS is characterized by progressive decrease in GFR and renal blood flow with marked intrarenal vasoconstriction in the presence of systemic vasodilatation. There are two types of HRS, type I and type 2; typical HRS-1 is the rapidly progressive AKI with 100 % increase in SCr to a level of >2.5 mg/dL or to 50 % decrease in GFR to a level of <20 mL/min within less than 2-week period. Type-2 HRS which is considered as a form of CKD is mostly observed in patients with ESLD and ascites which is slowly progressive AKI with SCr of >1.5 mg/dL [29]. Although the exact etiology of HRS is still not fully understood, there are multiple factors that operate together in the development of the HRS. These factors are systemic vasodilatation with hyperdynamic circulation, stimulation of renal sympathetic system and activation of RAS, low renal perfusion pressure due to possible cirrhotic cardiomyopathy, and finally the role of different pro-inflammatory cytokines on renal blood flow and renal function.

Table 34.3
Diagnostic criteria of HRS (IAC)

Major criteria: Only one major criterion is required to establish the diagnosis of HRS

1. Low GFR, as indicated by SCr >1.5 mg/dL or 24-h creatinine clearance <40 mL/min

2. Absence of shock, ongoing bacterial infection, fluid losses, and current treatment with nephrotoxic drugs

3. No sustained improvement in renal function (decrease in serum creatinine to ≤1.5 mg/dL or increase in creatinine clearance to ≥40 mL/min) after diuretic withdrawal and expansion of plasma volume with 1.5 L of a plasma expander

4. Proteinuria <500 mg/day and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

Additional criteria

1. Urine volume <500 mL/day

2. Urine sodium <10 mEq/L

3. Urine osmolality greater than plasma osmolality

4. Urine red blood cells <50/high-power field

5. Serum sodium concentration <130 mEq/L

Overall, the development of HRS-1 is usually due to precipitating factors such sepsis, aggressive paracentesis, GI bleed, or surgery [30]. These factors can lead to further deterioration of cardiac output and renal blood flow as well as excessive production of multiple mediators that further compromised the delicate renal hemodynamics with the end result of HRS-1. However, in HRS-2 or CKD there is no clear precipitating factor but overall slow-progressive deterioration of the renal function coupled with gradual increase in renal vascular resistance [28, 29]. According to the IAC definition of HRS-1 to establish the diagnosis of HRS-1, three major criteria are required (Table 34.3). However, to differentiate the HRS-1 from ATN by relying on the urinary sodium excretion or presence of proteinuria indices can be unreliable. The prognosis of HRS-1 is very poor with almost 80 % mortality within 4 weeks. HRS-2 has much better prognosis with the median survival rate around 6 months. The prognosis of both types is dependent on the severity of liver diseases (high MELD or Child-Pugh scores) as well as the presence of the precipitating factors [26, 31].

Intrinsic Renal Diseases

Nephrotoxic Agents

The aminoglycoside antibiotics are notorious for causing renal damage through their effects on renal tubules and glomeruli [32]. The aminoglycoside-induced renal toxicity is characterized by non-oliguric or polyuric renal failure with increased urinary loss of glucose, protein, and electrolytes. As expected aminoglycoside nephrotoxicity is more frequent and severe in patients with ESLD due to underling AKI. Other antibiotics that are implicated in nephrotoxicity include penicillin, acyclovir, and amphotericin [33].

The contrast-induced nephropathy (CIN) is a well-known complication following any diagnostic or therapeutic interventions where the CIN is used. The etiology of CIN is probably multifactorial, either direct toxic effects on the renal tubules or renal vascular spasm due to hyperosmolality and high viscosity and/or through the release of toxic free radicals. CIN tends to occur in patients who are at high risk to develop AKI as in diabetic patients, old age, and ESLD or in any patient with underlying kidney disease. Recently, the incidence of CIN is reduced since the introduction of nonionic iso-osmolal or low osmolal agents and with the use of smaller doses of the agent. In patients with ESLD, the use of the contrast media should be restricted or completely avoided unless it is extremely necessary and only in cirrhotic patients with normal renal function [34].

Chronic Glomerulonephritis

Viral hepatitis and in particular hepatitis C cirrhosis are leading causes of glomerular pathology. Hepatitis B cirrhosis can cause glomerulonephritis which is seen mostly in endemic areas and where the HBV surface antigen carrier state is fairly common. In both types of viral hepatitis the glomerular involvement shows a wide spectrum of pathological changes that can affect the glomerular membrane or the vascular parts of the glomerulus [35, 36].

IgA Nephropathy

The primary form of IgA nephropathy is usually presented with proteinuria and hematuria due to deposit of the globular IgA in the renal mesangium and in the glomerular capillaries. In patients with ESLD and especially in alcoholic cirrhosis there is high level of serum IgA and the development of subclinical IgA nephropathy is fairly common. The possible explanation for IgA nephropathy in patients with ESLD may be related to decreased hepatic clearance of the protein complex and impaired phagocytic function of Kupffer cells [37].

Diabetic Nephropathy

Diabetes type 1 and 2 are common etiologies for nephropathy and in patients with ESLD there is high prevalence of glucose intolerance and diabetes especially in patients with nonalcoholic steatohepatitis. Diabetic nephropathy is commonly diagnosed in patients with ESLD as part of metabolic syndrome which is related to obesity [38].

Jul 9, 2017 | Posted by in Uncategorized | Comments Off on Renal Dysfunction in Hepatic Failure
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