Saudi Journal of Kidney Diseases and Transplantation

: 1996  |  Volume : 7  |  Issue : 3  |  Page : 277--282

Hepatorenal Syndrome

Paul Sweny 
 Department of Nephrology and Transplantation, Trie Royal Free Hospital, London, United Kingdom

Correspondence Address:
Paul Sweny
Department of Nephrology and Transplantation, The Royal Free Hospital, Pond Street, London MW3 2GQ
United Kingdom


The hepatorenal syndrome (HRS) is a common complication of advanced liver disease. Careful management can reduce the risk of this functional renal failure developing in the vulnerable group of patients. Potentially nephrotoxic agents (drugs, x-ray contrast, etc.) need to be avoided wherever possible. It is likely that sympathetic overactivity, endotoxin, nitric oxide and endothelin, together with perturbed arachidonic acid metabolism, are closely involved in pathogenesis. Many of the associated abnormalities in HRS can be explained on the basis of an inadequate effective arterial blood volume and the resulting attempts at compensatory homeostasis. Medical management is disappointing, but trans-cutaneous intra-hepatic portal systemic shunting may help. Successful orthotopic liver transplantation is curative.

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Sweny P. Hepatorenal Syndrome.Saudi J Kidney Dis Transpl 1996;7:277-282

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The hepatorenal syndrome (HRS) is defined as a functional acute renal failure (ARF) that usually develops in the context of severe liver disease with edema and ascites. Part of thedefinition includes the failure of the ARF to respond to a volume challenge and the functional nature of the ARF is reflected in the absence of any structural changes in the kidney and a quiet urine deposit [1],[2] .

 Clinical Features

There are three major conditions that are generally associated with the HRS. They are advanced cirrhosis from any cause, alcoholic hepatitis and fulminating acute liver failure; The condition can occur in any severe liver disease and may occasionally be seen following major hepatic resection. The clinical features are essentially those of the primary liver disease [3] . Of particular note are the low blood pressure, warm peripheries and bounding pulse, reflecting a low systemic vascular resistance (SVR). Edema and as cities are usually Present and the Stigmata of advanced liver disease are common (liver palms, spider naevi, etc.).

 Precipitating Factors

The HRS rarely develops out of the hospital setting implying that it is provoked by iatrogenic factors. The over-zealous use of diuretics, paracentesis without protection of the intravascular volume, sepsis, and bleeding from varices are well recognized provoking events. Characteristically, the condition develops insidiously without a catastrophic acute event, unlike acute tubular necrosis.


The pathogenesis of HRS is complex and not fully elucidated [4] . The condition is dependent upon the liver disease as renal recovery follows orthotopic liver transplantation (OLT) [5] . Conversely, patients dying with liver disease and HRS have been used as kidney donors with rapid recovery of renal function following transplantation of the kidney [6] . The accepted view is that the spectrum of liver disease, from early compensated cirrhosis through decompensated liver disease (ascites and edema) to the HRS, is all part of the same process. In other words, if we understand the mechanisms responsible for the development of edema and ascites in liver disease, then we will be a long way towards understanding the pathogenesis of the HRS. Pathogenesis can be divided into three general areas; hemodynamic, neural and humoral.

Hemodynamic Factors

Hemodynamically, there is a marked fall in SVR early in progressive liver disease [7] . In some patients, this may antedate sodium retention. The fall in SVR is due to systemic vasodilatation and arterio-venous shunts in skin, muscles and lungs. There is also a marked increase in splanchnic arterial inflow, which develops in response to portal hypertension and the development of porto-system-ic shunts [8] . These shunts compromise the integrity of the effective arterial blood volume (EABV). Contraction of the EABV activates sodium retaining mechanisms [9] . These include the sympathetic nervous outflow, the renin­-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP).

Neural Factors

Early in liver disease, associated with the rise in hepatic wedge pressure, there is an increase in vagal afferents from the liver which activates the sympathetic outflow, particularly to the kidney [10] . This increased sympathetic activity to the kidney increases sodium retention, reduces cortical blood flow and may also cause afferent glomerular arteriolar constriction. It is thought that this reflex is at least partly responsible for primary sodium retention which can precede ascites formation (the overfill theory) in animal studies [11] . Several imaging techniques have shown marked intra-renal vasoconstriction and vascular instability of the renal circulation to be typical of this syndrome. Contrast studies after death have shown a normal intra-renal arterial tree.

Humoral Factors

The humoral abnormalities noted in HRS are summarized in [Table 1]. Several words of caution must be uttered before these abnorm­alities can be sensibly interpreted. Some of the observed abnormalities are more by way of compensatory responses and are not etiological or first movers. In such cases, blockade of the particular pathway may aggravate or provoke HRS and have no therapeutic benefit. Thus, it is well recognized that angiotensin converting enzyme inhibitors (ACE-I) and the non­steroidal anti-inflammatory drugs can precipitate HRS in susceptible patients. There is a marked reduction in end-organ responsiveness to vasoconstrictors in the HRS, probably due to post-receptor effects [12] . The kidney has increased sensitivity to the activity of aldosterone, but reduced sensitivity to atrial natriuretic peptide. Thus, altered end-organ responsiveness must be considered in the pathogenesis of HRS. It is also clear that different vascular beds respond differently to the various vasoactive agents; e.g., the renal vasculature is particularly sensitive to the vasoconstricting effects of endothelin. When interpreting the urinary excretion of various mediators (e.g., prostaglandins), correction has to be made for glomerular filtration rate. It is also becoming relevant that many of the original physiological studies done in HRS were carried out with the patient supine rather than erect. The further exacerbation of an inadequate EABV on standing makes interpretation of much of the data in the literature difficult.

The range and diversity of the humoral agents produced by the endothelium is only just becoming apparent. The importance of sheer stress (flow rates) in stimulating release is emerging. It is also now known that the release of, for example a vasoconstricting agent, will be opposed by the simultaneous release of a vasodilator and vice versa in a complex feed­back regulation system [13] .

There are two interesting paradoxes in the HRS. What agent is it that can cause intense renal vasoconstriction, yet marked peripheral vasodilatation? Secondly, what is the mechanism of the increased splanchnic arterial inflow in the face of portal hypertension and outflow obstruction? It is still not yet possible to be clear about the initiating neuro-humoral abnormalities in HRS and what are merely compensatory responses. What follows is an attempt to point out likely major etiological factors. There is clear evidence of early sympathetic overactivity in HRS with the initiating event appearing to be portal hypertension stimulating vagal affer-ents from the liver [14] .

It is also well established that endotoxin levels are raised in HRS [15] along with the related release of cytokines (tumor necrosis factor-alpha, interleukins 1 and 6) [16] . Elevated systemic endotoxin levels reflect increased absorption from the gut (congestion) and spill over (shunting) from the portal circulation to the systemic circulation as well as impaired clearance of endotoxin by the diseased liver. Endotoxin is a potent trigger for the release and production of endothelin [17] . Nitric Oxide and the products of the arachidonic acid metabolic cascades are also increased by endotoxins [18],[19] . It seems likely that the elevated urinary excretion of PGI2 metabolites and PGE2 reflect increased renal production of vasodilating prostaglandins produced in compensation for renal vasoconstriction. It seems unlikely that they contribute to systemic vasodilatation. Other products of the arachi-donic acid cascade may be important in producing renal vasoconstriction. Thus, the production of thromboxane A2 [20] , the leukotrienes C4 and D4 [21] and the F2 isoprostanes [22] are increased in HRS and produce not only renal vasoconstriction, but can also produce contraction of the mesan-gium, thereby reducing the filtration coefficient in the glomerulus. An imbalance between TXA2 (vasoconstriction) and PGI2 /PGE2 (vasodilatation) may be important [23] . Widespread release of nitric oxide in both splanchnic and systemic circulation seems likely to be responsible for the reduction of SVR and splanchnic hypere-mia. Both calcitonin gene related peptide [24] and glucagon [25] are important in contributing to the splanchnic arterial vasodilatation.


Treatment is unsatisfactory. Prognosis is governed entirely by the potential for recovery of the liver disease. Patients die with, but not of, renal failure. No single pharmacological agent is completely effective at reversing HRS. Recently, the use of noradrenaline combined with dopamine has been shown to reduce SVR while reversing renal vasoconstriction [26] . Analogues of AVP in pharmacological doses, can indeed reverse HRS when given either in the short-term or by continuous infusion [27],[28] . This suggests that AVP release (non-osmotic) is a compensatory mechanism of insufficient magnitude to protect from the HRS. Certainly, blocking AVP in animal models impairs renal function. AVP analogues may work by reducing splanchnic hyperemia and reducing SVR. The use of TxA2 receptor blockers is promising [29] . PGE2 and PGI2 do not work [30] .

Although somatostatin analogues can reduce glucagon and splanchnic hyperemia, renal function is not improved [31] . Dopamine by itself is only transiently effective. A single report indicates that unilateral lumbar sympathectomy can restore renal function in a study of five patients [32] . Clonidine has been shown to improve renal function [33] . The last two observations suggest that the overactivity of the sympathetic nervous system is important in the pathogenesis of HRS.

The role of peritoneo-venous shunts [34] or porto-systemic shunts [35] is rapidly diminishing in view of the great morbidity and mortality associated with these surgical techniques. Neither technique has been shown to prolong survival. Introduction of transcutaneous intra-hepatic portal systemic shunting (TIPS) has renewed interest in surgical therapy [36] . Creating a large intra­hepatic porto-systemic shunt actually im­proved renal function in most cases despite the risk of a further reduction in SVR. TIPS is not without risks (encephalopathy and hemorrhage) but at least it does not make subsequent OLT more hazardous. The only really effective treatment for HRS is OLT unless the liver disease recovers [37] . It follows from this that renal support is palliative and can be only justified if the patient is a candidate for OLT or if there is a realistic chance of recovery of the primary liver disease. When renal support is provided, great care is needed. Continuous arteriovenous hemofiltration is preferable to intermittent hemodialysis. Careful attention to technique and choice of membranes is important to minimize the risks of cerebral hypoperfusion and cerebral edema [38],[39]


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