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 Table of Contents  
SYMPOSIUM
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 51-59

Cardiorenal and hepatorenal syndrome


1 Sr. Consultant, PICU, Nelson Mother and child care Hospital, Nagpur, India
2 Consultant, PICU, Nelson Mother and child care Hospital, Nagpur, India
3 Fellow, PICU, Nelson Mother and child care Hospital, Nagpur, India
4 Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, India

Date of Submission06-Apr-2018
Date of Acceptance19-Apr-2018
Date of Web Publication30-Apr-2018

Correspondence Address:
Anand Bhutada
Consultant Pediatric & Neonatal Intensivist, Central India's Child Hospital and Research Institute, Shreevardhan Complex, Ramdaspeth, Nagpur 440012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.21304/2018.0502.00374

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  Abstract 


Cardiorenal syndrome(CRS) is an interdependent involvement of the heart and the kidney that leads to high morbidity, recurrent readmissions and grave prognosis. Early use of slow high-dose intravenous diuretics, dialysis with ultrafiltration for treatment of congestion, inotropes and left ventricular assistant device to stabilize the hemodynamics and maintenance of the renal perfusion are the vital component for a short period of time. Hepatorenal syndrome (HRS) is a unique form of functional renal failure associated with progressive liver failure. It carries worst prognosis among all causes of renal failure in children with liver disease. Liver transplantation is the definitive treatment of HRS. Vasoconstrictor therapy with albumin and Renal replacement therapy are used as a bridge to liver transplant for patients who are unresponsive to medical therapy.

Keywords: Cardiorenal syndrome, Hepatorenal syndrome, dialysis, ultrafiltration.


How to cite this article:
Bhutada A, Choudhary A, Kapse A, Patki V. Cardiorenal and hepatorenal syndrome. J Pediatr Crit Care 2018;5:51-9

How to cite this URL:
Bhutada A, Choudhary A, Kapse A, Patki V. Cardiorenal and hepatorenal syndrome. J Pediatr Crit Care [serial online] 2018 [cited 2020 Mar 29];5:51-9. Available from: http://www.jpcc.org.in/text.asp?2018/5/2/51/281121




  Cardiorenal Syndrome Top


Cardiorenal syndrome is a set of clinical and metabolic conditions where acute or chronic reduced function of either the heart or the kidney induces acute or chronic dysfunction in the other organ. Patients with cardiorenal syndrome (CRS) suffer from extremely high levels of morbidity and mortality. The pathophysiology of the CRS involves inter-related hemodynamic and neurohormonal mechanisms including the renin angiotensin aldosterone system (RAAS), endothelin, and arginine vasopressin system activation. The management of CRS remains a challenge despite extensive research into the pathophysiology, discovery of new biomarkers, and ongoing drug trials. This syndrome is associated with unfavorable outcomes in adults. The literature suggests similar poor outcomes in children.

Cardiorenal syndrome (CRS) is a relatively new term introduced to describe the heart and kidney comorbid state that has been long known and frequently managed in very sick individuals. It is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ induces acute or chronic dysfunction of the other.[1],[2] The 7th Acute Dialysis Quality Initiative Workgroup recently standardized the classification of CRS into five distinct clinical types.[1],[2] These are namely: Acute CRS (CRS Type 1 or CRS-1) - acute worsening of heart function leading to acute kidney injury (AKI) and/or dysfunction; chronic CRS (CRS Type 2 or CRS-2) - chronic abnormalities in heart function leading to kidney injury and/or dysfunction; acute renocardiac syndrome (CRS Type 3 or CRS- 3) - acute worsening of kidney function leading to heart injury and/or dysfunction; chronic renocardiac syndrome (CRS Type 4 or CRS-4) - chronic kidney disease leading to heart injury, disease and/or dysfunction; and secondary CRS (CRS Type 5 or CRS-5) - systemic conditions leading to simultaneous acute or chronic injury and/or dysfunction of heart and kidney.

Biomarkers can contribute to an early diagnosis of CRS and to a timely therapeutic intervention. The use of this classification can help physicians characterize groups of patients, provides the rationale for specific management strategies [1]

Epidemiology:

Currently, the incidence of CRS in children is unknown as very little work has been done in this area, in spite of the fact that heart failure is a common comorbidity in renal failure.[1] Complications of acute or chronic renal dysfunction and vice versa revealed that CRS prevalence could range between 3.0% and 52.0% [3],[4],[5],[6]

Pathophysiology:

In CRS, the impaired forward flow and decreased effective circulating volume in case of severe systolic HF or cardiogenic shock lead to arterial underfilling and activation of neurohormonal and inflammatory pathways, resulting in fluid retention and increase in venous pressure (VP) and important repercussions on renal perfusion. Autoregulation of the GFR fails and kidney function declines, subsequently leading to worsening fluid retention, preload, and afterload. A series of maladaptive responses including the activation of the rennin angiotensin aldosterone system (RAAS), tubuloglomerular feedback, and activation of sympathetic nervous system occur in heart failure (HF).[7] Furthermore, venous congestion and high right-sided pressure, such as in the case of HF with preserved ejection fraction (EF) or isolated right HF, may lead to decreased arteriovenous perfusion gradient, increased kidney interstitial edema, and worsening of fluid retention.[7],[8] A higher central VP (CVP) was found to be inversely related to GFR and independently associated with all- cause mortality.[9] Moreover, an incremental risk of developing worsening renal failure (WRF) with increasing CVP was observed in patients with acute decompensated heart failure (ADHF) independent of the cardiac output (CO). Thus, further understanding of the role of increased VP in CRS may provide future novel drug targets and gauge therapeutic efficacy. CRS is a systemic illness that results from the interplay among myocardial factors, systemic inflammation, renal dysfunction, and neurohormonal activation including adenosine, endothelin, and decreased response to atrial natriuretic peptide (ANP). Insights into the pathophysiology of HF have allowed the identification of several biomarkers that represent key disease pathways. Among others, promising biomarkers identified for this purpose include cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-b-D-glucosaminidase, and kidney injury molecule-1.(10-12) The application of these biomarkers may provide future therapeutic modifications aiming at an earlier stage, thereby attenuating further damage to the kidneys.

Classification:

Acute Cardiorenai Syndrome: Type I

This appears to be a syndrome of worsening renal function that frequently complicates hospitalized patients with acute decompensated heart failure (ADHF) and acute coronary syndrome.

One study proposed that patients with renal dysfunction had a significantly increased risk (almost 4 times) of developing an adverse outcome (recurrent acute coronary syndromes, revascularization, left ventricular failure, death) after AMI. This entity has specific treatment and prevention strategies.

Preventive Approaches

The basic principles include avoidance of volume depletion, removal of superimposed renal toxic agents (NSAIDs agents, aminoglycosides), minimization of the toxic exposure (iodinated contrast, time on cardiopulmonary bypass) and possibly, the use of antioxidant agents such as N-acetylcysteine and BNP in the perioperative period after cardiac surgery. Use of continuous renal replacement therapy (CRRT) provides three important protective mechanisms that cannot be achieved pharmacologically as follows: (a) it ensures euvolemia and avoids hypo- or hypervolemia; (b) it provides sodium and solute (nitrogenous waste products) removal and (c) by both mechanisms above, it may work to avoid both passive renal congestion and a toxic environment for the kidneys.

Table 1 : Classifi cation of cardiorenal syndrome proposed by Ronco et al[1]

Click here to view


Management

Type I CRS appears in the setting of ADHF or cardiogenic shock for a number of reasons, with hemodynamic derangements ranging from acute pulmonary edema with hypertension through severe peripheral fluid overload to cardiogenic shock and hypotension. The goal of diuretic use should be to deplete the extracellular fluid volume at a rate that allows adequate time for intravascular refilling from the interstitium. To achieve adequate diuresis, infusions of loop diuretics have been demonstrated to have greater efficacy than intermittent dosing. If kidney function continues to worsen, blockade of the RAAS may be a contributing factor, necessitating withholding or delaying the introduction of angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in order to maintain the GFR.

For Type I CRS patients with preserved or elevated blood pressure, vasodilators such as nitroglycerin and nitroprusside are often used to relieve symptoms and improve hemodynamics. When patients have low blood pressure and poor renal perfusion, positive inotropes such as dobutamine or phosphodiesterase inhibitors may be required.

Chronic Cardiorenal Syndrome: Type II

This subtype is a separate entity from acute CRS as it indicates a more chronic state of kidney disease complicating chronic heart dis ease. This is an exceptionally common problem. For instance, in patients hospitalized with congestive heart failure (CHF), approximately 63% meet the kidney disease outcomes quality initiative (K/DOQI) definition of stages 3-5 CKD (eGFR < 60 mL/min/1.73 m2).

Preventive Approaches

Pharmacologic therapies that have been beneficial for chronic CVD have been either neutral or favorable to the kidneys including use of RAAS antagonists, beta- adrenergic blocking agents and statins. Furthermore, other strategies including glycemic control in diabetes and blood pressure control in those with hypertension.[13]

Management

Interruption of the RAAS is the primary aim in the management of Type II CRS. However, RAAS blockade can lead to significant decrease in kidney function and/or elevated potassium. However, creatinine tended to stabilize, and in many instances, improved over the course of the study. In terms of aldosterone blockade, drugs such as spironolactone and eplerenone are important adjuncts to therapy in patients with severe heart failure. Both CHF and CKD are associated with anemia, which is commonly treated with erythropoiesis-stimulating agents. Furthermore, the action of erythropoietin in the heart may reduce apoptosis, fibrosis and inflammation. Hence, there has been intense interest in using erythropoiesis- stimulating agents in heart failure patients.

Acute Renocardiac Syndrome: Type III

Although AKI is documented as an important cause of acute heart disorder, the pathophysiological mechanisms likely go beyond simple volume overload and hypertension, and the recent consensus definition for AKI will aid in the investigation and analysis of epidemiologic data. The development of new biomarkers, and the study of prevention and management strategies in AKI following radiocontrast or cardiac surgery, will increase our knowledge of this syndrome.

Preventive Approaches

The major management principle concerning this syndrome is intra- and extravascular volume control with either use of diuretics and forms of extracorporeal volume and solute removal (CRRT, ultrafiltration, hemodialysis).

Management

In Type III CRS, AKI occurs as a primary event (e.g. acute glomerulonephritis) or secondary event (e.g.radiocontrast, exogenous or endogenous nephrotoxins, postsurgical, etc.) and cardiac dysfunction is a common and often at times fatal sequelae. A common example of Type III CRS occurring in the hospital setting is contrast nephropathy, particularly in patients undergoing coronary and other angiographic procedures who have risk factors such as pre-existing CKD, diabetes, older age or volume contraction. In these susceptible populations, prevention may provide the best opportunity to “treat” or avoid Type III CRS. Many potential preventive strategies have been studied, including parenteral hydration (hypotonic or isotonic saline or bicarbonate), diuretics, mannitol, natriuretic peptides, dopamine, fenoldopam, theophylline and N-acetylcysteine. Treatment of primary kidney diseases such as acute glomerulonephritis or kidney allograft rejection may potentially lessen the risk of Type III CRS, but this has not been systematically studied. Furthermore, many immunosuppressive drugs used for such treatment have adverse effects on the cardiovascular system through their effects on blood pressure, lipids and glucose metabolism.

Chronic Renocardiac Syndrome: Type IV

A large body of evidence has accumulated demonstrating the graded and independent association between level of CKD and adverse cardiac outcomes.

Preventive Approaches

Optimal treatment of CKD with blood pressure and glycemic control, RAAS blockers and disease- specific therapies, when indicated, are the best means of preventing this syndrome. Morbidities of CKD, including bone and mineral disorder and anemia, should be managed according to CKD guidelines.

Management

The management of Type IV CRS is a multifaceted approach focusing on the decline of cardiovascular risk factors and complications common to CKD patients. These include, but are not limited to, anemia, hypertension, altered bone and mineral metabolism, dyslipidemia, smoking, albuminuria and malnutrition. Several therapies targeting such uremic complications as anemia, homocysteine, calcium- phosphate product and hyperparathyroidism are supported by observational studies demonstrating the association between adverse cardiovascular events and these conditions.

Secondary Cardiorenal Syndromes: Type V

This subtype does not have a primary and secondary organ dysfunctions, situations do arise where both organs simultaneously are targeted by systemic illnesses, either acute or chronic. Examples include sepsis, systemic lupus erythematosus (SLE), amyloidosis and diabetes mellitus.

Preventive Approaches

There are no proven methods to prevent or ameliorate this form of CRSs at this time. Supportive care with a judicious intravenous fluid approach and the use of pressor agents as needed to avoid hypotension are reasonable but cannot be expected to avoid AKI or cardiac damage.

Management

Examples of Type V CRS include a heterogeneous group of disorders such as sepsis, SLE, amyloidosis and diabetes mellitus. It is difficult to formulate a treatment strategy to encompass all of these disorders, but more important is the recognition that injury to one organ is likely to influence or injure the other organ and vice versa. Therapies directed to the improvement in function of one organ need to consider the interaction with, and role of the other. Sepsis is one of the more common acute disorders that involves multiple organs, and often causes co-dysfunction of kidneys and heart. Recognition of Type V CRS as an entity in sepsis and other systemic disorders will allow further research into the signaling and mechanisms of injury, and allow for the development of rational and efficient therapies.

Therapeutic considerations

Potentially promising pharmacological approaches include selective adenosine A1 receptor blockers, which have a variety of effects on intrarenal hemodynamics and tubular function[14] and vasopressin antagonists (V2 receptor antagonists “vaptans”, e.g. conivaptan and tolvaptan).[15] Adenosine can lower cortical blood flow, resulting in antinatriuretic responses. A1 receptor antagonists Rolophyline have been shown to cause diuresis and natriuresis while minimally affecting potassium excretion or glomerular filtration Levosimendan is a promising treatment, which is an inotrope independent of the badrenergic receptors; however, this has been showing inconsistent results in the treatment of acute CRS. Further studies are thus required to determine whether repetitive dosing of levosimendan will benefit the survival of patients with stable advanced CRS.[16],[17] Patients with diuretic refractoriness may benefit from mechanical removal of fluid (ultrafiltration, UF). Two modalities of renal replacement therapy can be used in these patients, namely, isolated UF and peritoneal dialysis (PD). Ultimately, left ventricular assist devices LVAD) has been used as a bridge to heart transplant or as a “designation treatment” for those unsuitable for receiving a transplant to manage these patients effectively, at least in the short-term.

Novel agents

Serelaxin is a recombinant form of human relaxin-2. This is a naturally occurring peptide hormone that increases during pregnancy and mediates the maternal physiological CV and renal adaptations and has potential protective effects against organ damage. It is a functional endothelin-1 antagonist and its role in CRS is being studied.[18]

Neprilysin is a neutral endopeptidase that catalyzes the degradation of a number of vasodilator peptides, including ANP, BNP, bradykinin, substance P, and adrenomedullin, and contributes to the breakdown of angiotensin II.[19] Therefore, inhibiting this enzyme will augment the naturally occurring NP. Because neprilysin inhibitors may potentially increase circulating angiotensin II levels, it provides a rationale for developing a compound that dually blocks this enzyme and the RAAS.

Aliskiren, a direct renin inhibitor, represents another pharmacologically distinct method for RAAS blockade with the theoretical benefit of upstream RAAS inhibition at the point of pathway activation.[20]

To conclude

CRS is a growing health problem and is associated with high morbidity and mortality. There is the need for collaborative work on childhood CRS between pediatric cardiologists, nephrologists and intensivists to better understand the syndrome so that a well coordinated therapeutic program can be developed for universal application. Simultaneous management of heart and renal failure in CRS is quite challenging; the therapeutic choice made for one organ must not jeopardize the other.


  Hepatorenal Syndrome Top


Acute kidney injury is a common complication of progressive liver disease. The vascular and hemodynamic changes which occurs in body in progressive liver disease profoundly impacts the kidney. Hepatorenal syndrome (HRS) is a unique form of functional renal failure which is reversible and occurs in histologically normal kidneys. It results from diminished renal blood flow and is not responsive to volume replacement.[21] It’s a grave complication of advanced liver disease with worst prognosis among the causes of renal failure in patients with cirrhosis and ascites. It also occurs with acute liver failure.

Pathophysiology[21],[22] : HRS occurs due to unique mechanism resulting in reduced renal blood flow in patients of cirrhosis with ascites or severe liver dysfunction. The peripheral arterial vasodilatation theory is the most widely accepted theory for HRS. In patients with cirrhosis resultant portal hypertension leads to increased production of vasodilators (nitric oxide, glucagon, carbon monoxide, vasodilator peptides etc) thereby causing splanchnic vasodilation. The blood gets sequestered in splanchnic vascular bed leading to reduced effective arterial blood volume i.e arterial underfilling. The vasodilators get redirected to systemic circulation further leading to systemic hypotension. In the compensated cirrhosis stage, cardiac contractility and output increases to counterbalance this reduction in systemic vascular resistance. Also, as a compensatory mechanism neurohormonal vasoconstrictor systems such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervoussystem (SNS), and arginine vasopressin are stimulated causing vasoconstriction of cerebral, renal, peripheral vascular beds and ascites and hyponatremia by causing sodium and water retention.The end result of this process is a severe decline in renal blood flow leading to reduced glomerular filtration rate (GFR) and the developmentof HRS.

Clinical features

In HRS, renal failure sets in patients of acute liver failure or chronic liver failure with portal hypertension who are complicated by jaundice, ascites, encephalopathy and coagulopathy. Patients develop oliguria with elevated creatinine unresponsive to volume replacement. Concomitant bacterial infection can be there but there is absence of shock. Two types of HRS is described and they differ in rate of progression and severity.[23]

Type 1 HRS is mostly associated with acute liver failure or alcoholic cirrhosis in adults and is characterized by rapidly progressive renal failure mostly within 2 weeks with multiorgan dysfunction. It is usually followed by a precipitating event like bacterial peritonitis, UTI or cellulitis.

Type II HRS is insidious in onset and renal failure sets in weeks and it is usually associated with recurrent diuretic resistant ascites. Both types of HRS has a poor prognosis.

The diagnostic criteria of HRS by International Ascites Club (IAC) which was revised in 2007 for adults is as follows.[24]

  • Cirrhosis with ascites
  • Serum Creatinine > 1.5 mg/dL
  • Absence of shock
  • No improvement of serum creatinine (decrease to a level of 1.5 mg/dL or less) after at least 2 days of diuretic withdrawal and volume expansion with albumin
  • No current or recent exposure to nephrotoxic drugs
  • Absence of parenchymal disease as indicated by proteinuria > 500 mg/d, microscopic hematuria (50 red blood cells per high power field) and abnormal renal ultrasonography


Management:

Currently available therapies enhance the short-term survival of HRS patients. Patients with hepatorenal syndrome especially Type I HRS patients require hospitalization and aggressive management considering the dismal prognosis.Intravascular volume status can be assessed by insertion of central line. It is very essential to rule out precipitating factors or other factors for acute renal failure (ARF) especially spontaneous bacterial peritonitis (SBP). Special consideration should be given to nutrition in these patients, low salt diet should be emphasized, high protein intake may precipitate hepatic encephalopathy or metabolic disturbances. The therapeutic armamentarium includes specific vasoconstrictive agents, TIPS (transjugular intrahepatic portosystemic shunts), renal replacement therapies and liver transplantation. Liver transplant remains the only truly effective treatment but is limited by the high mortality rate

Vasoconstrictor therapy: is the primary medical treatment available for HRS. They are used as a bridge to liver transplantation or may be the only option in patients in whom liver transplantation is not feasible. They act by causing vasoconstriction ofthe splanchnic vessels resulting in increased systemic vascular resistance thereby causing suppression of RAAS and sympathetic nervous system leading to improved renal perfusion.[21] A metanalysis reported improved survival with vasoconstrictor therapy.[21] The Acute Dialysis Quality Initiative (ADQI) work group recommends the use of vasoconstrictor drugs combined with plasma expansion with albumin, as first line treatment for type1 HRS.[25] The recommended vasoconstrictor drugs for HRS are Terlipressin, Norepinephrine and midodrine (in combination with octreotide)used along with albumin infusion. Albumin augments the potency of vasoconstrictor drugs by improving cardiac function and increasing the effective arterial blood volume. Terlipressin is recommended first line treatment in Type 1 HRS with limited experience for Type 2 HRS.[24] Use of Terlipressin with albumin significantly increases its efficacy.[26] This combination may be effective in Type 2 HRS also. The treatment response is seen clinically in the form of increasing mean arterial pressure (MAP) with increase in urine volume and increase in serum sodium with decrease in serum creatinine. The median response time is around 2 weeks.[27] Pediatric data on use and dosage of terlipressine is limited. In case series of 4 children terlipressine used in dose of 30ug/kg/day as continuous infusion led to rapid improvement of renal function with no adverse effect noted in any child. Also terlipressine was used as a bridge therapy for liver transplantation in one child. Terlipressine used in continuous infusion is preferred to intermittent boluses though it needs to be studied further in trials.[28] In adults multiple randomized controlled trials and systematic review corroborated the effectiveness of terlipressine in reversing the HRS.[29],[30] as well as decreasing mortality due to HRS.[31],[32] Since terlipressine is costly drug, other drug, norepinephrine has been used as a vasoconstrictor agent for treating HRS. Norepinephrine is α adrenergic drug, acts via α1 adrenergic receptors in vascular smooth muscle cells. The efficacy of norepinephrine when compared to terlipressine was found to be same in randomized controlled trials conducted in adults.[33],[34],[35] Following withdrawal of treatment with vasoconstrictor therapy HRS may recur in around 20% to 50% although retreatment is generally effective.

Transjugular Intrahepatic Portosystemic Shunt (TIPS): The creation of portosystemic shunt increases return of splanchnic blood to right heart and increases the effective arterial blood volume thereby improving the renal perfusion in HRS patients. TIPS can be used in the short term as a bridge therapy for patients awaiting liver transplantation. The use of TIPS is limited due to its many contraindications and it may precipitate hepatic encephalopathy with aggravation of liver failure.

Extracorporeal support therapy: Renal Replacement Therapy (RRT) The indications of RRT in HRS is same as in other causes of AKI. It is used to treat metabolic acidosis, hyperkalemia, volume overload and uremic symptoms. RRT acts as a bridge to liver transplantation especially in patients unresponsive to vasoconstrictor therapy. Continuous renal replacement therapy (CRRT) in form of continuous venovenous hemofiltration (CVVH) is usually preferred to intermittent dialysis (IHD) due to its greater hemodynamic stability ensuring fewer fluctuations in intracranial pressure. Peritoneal dialysis can be used in patients where hemodialysis is not feasible to correct ascites and other complications of hepatorenal failure. The ADQI workgroup recommends that RRT should be avoided in type 1 HRS patients unless there is an acute reversible component or an intention to pursue transplantation.[25] RRT acts as a bridge to liver transplantation especially in patients unresponsive to vasoconstrictor therapy. A case control study in pediatric including infants found that RRT benefits patients with HRS and may enhance survival until liver transplantation occurs.[36]

Liver transplantation: LT remains the treatment of choice in HRS.[21] The five-year survival for HRS is 60% for patients that underwent liver transplantation comparedwith 0% for patients that did not undergo liver transplantation.[37] Between 58 and 94% of patients with HRS demonstrate recovery of renal function after liver transplantation.[38],[39],[40] The main limitation of liver transplantation is due to the shortage of donor organs. To conclude, HRS is a grave complication of acute/chronic liver disease and should be treated with vasoconstrictor agents with albumin, renal replacement therapy till liver transplantation is feasible. Diagnostic criteria for pediatric patients need to be defined. Pediatricians/gastroenterologists treating cirrhosis/ acute liver failure patients should pursue this diagnosis early and ensure prompt treatment to enhance survival.

Source of Funding - Nil

Conflict of Interest - Nil



 
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Cardiorenal Syndrome
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