Analysis of data from two randomized studies where information on causes of death in individual patients were available revealed that the majority of patients treated with terlipressin died either because of multi-organ failure or sepsis or Systemic Inflammatory Response Syndrome (SIRS) or hepatic failure.[7
] Reduction in the mortality rate due to HRS alone as cause of death even at three months was though low but significant. As terlipressin doesn’t reduce severity of underlying liver failure, its lack of survival benefits against liver failure as cause of death can be expected.[7
] Interestingly, survival benefits against multi-organ failure as cause of death was favored in control group; raising the doubt of possibility of increased incidences of deaths due to multi-organ failure in terlipressin group. Lack of survival benefits of terlipressin and perhaps with other vasoconstrictor drugs in HRS despite improvement in renal function may be attributed due either to their failure to prevent deaths due to other causes of death or increased incidences of deaths due to multi-organ failure. This might have been responsible for inter-individual and inter-study variations observed with survival benefits of terlipressin.
HRS reversal (decrease in serum creatinine< 1.5mg/dl) rate of terlipressin varies from 40 to 60%.[20
] The factors found to be favoring the HRS reversal or survival benefits in most of the randomized studies were HRS of type 2, young age, low baseline Child Pugh Score, low baseline Model for End-Stage Liver Disease (MELD) score, low baseline serum bilirubin, low baseline serum creatinine, high baseline creatinine clearance, alcoholic liver disease as etiology and significant rise in Mean Arterial Pressure (MAP) following treatment with terlipressin. Majority of patients who respond are those with mild renal failure (baseline serum creatinine<5mg/dl) and liver failure (Child Pugh score <11).[1
] And responder patients usually achieve a sufficient increase in MAP following treatment with terlipressin.[5
Interestingly, patients who respond to terlipressin still die of HRS.[21
] Reason why responders still die of HRS and how HRS can be reversed in non-responders needs to be explored.
An important factor that determines the responder and non-responder (failure achieve serum creatinine <1.5mg/dl after treatment) states is the baseline severity of renal failure. The reversal of HRS in patients with severe renal failure (baseline serum creatinine level >5mg/dl) is rare and early diagnosis of renal failure and immediate initiation of treatment with vasoconstrictors is advised.[5
] Perhaps the reason could be onset of subclinical renal tubular damage induced by long-term ischemia of kidney leading to a state of functional irreversibility.[22
] Failure of kidney to return from this point of irreversibility as a reason for non-responder state in patients with severe renal failure could be forwarded. Early treatment may thus prevent the onset of state of irreversibility or tubular damage and thus non-responder state to the vasoconstrictor drugs. However the question of treating non-responder patients who present with possible already set irreversible state remains to be answered. A pharmacological agent that needs to be explored to improve renal function in non-responders is the use of N-Acetylcysteine (NAC). NAC used alone in HRS has improved the renal function and survival rates.[23
] Mechanism behind improvement in renal function by NAC remains unknown as no improvement in severity of liver failure or hemodynamic derangements were observed in the study. An indirect evidence for possible beneficial effects of NAC in non-responders to terlipressin comes from a case report using combination of nonspecific endothelin receptor antagonist bosentan with NAC.[24
] Combination of these two drugs was found to be beneficial in improving renal function in a patient not responding to terlipressin. However whether the beneficial effects so observed was attributable to bosentan was doubtful. We are of the opinion that the beneficial effect so observed perhaps are attributable to NAC alone, not to bosentan as treatment with another non-specific endothelin receptor anatagonist tezosenton alone has not only failed to improve renal function, but also deteriorated the renal function.[25
] In addition, by its ability to reduced renal oxidant stress, NAC is known to prevent renal tubular damage induced by radiocontrast agents.[26
] Perhaps the same mechanism could have been responsible behind observed improvement in renal function with NAC in HRS. Role of oxidative stress in inducing both renal dysfunction and state of vascular non-reactivity in HRS and our concept of reversing them by antioxidants is also supported by few preliminary studies.[27
As found in most of the randomized studies, incidences of HRS reversal and survival rate were also related to the severity of liver failure (Child Pugh score >11). Influence of severity of liver failure on both survival and HRS reversal rate has also been emphasized.[30
] Bringing down the severity of liver failure in non-responder patients with CP score >11 may be essential in order to observe beneficial effects in this group of patients. Alternatively, decreasing the severity of liver failure and indirectly renal failure by this way may either help in making the patients suitable for surgical treatment with better outcome expected. Though liver transplantation treats the primary problem of hepatic failure, it may not be indicated or affordable by all patients. A pharmacological agent that decreases the severity of liver failure in patients with Child Pugh score >11 could be worth using in these patients. Such agent could again be NAC; though it has been found not to have any effect on severity of liver failure in HRS. Being antioxidant, NAC may exert indirect beneficial effects at least on deleterious manifestations of liver failure as does the albumin.[31
] Unlike the possibilities of reversing renal failure, benefits of NAC in bringing the non-responsive state to responsive state by altering severity of liver failure in severe/irreversible end stage cirrhosis is doubtful. However in the background of increased oxidative stress in the onset of multi-organ failure associated with liver failure, the most common cause of death in HRS and possible increased incidences of deaths due to multi-organ failure associated with use of terlipressin, addition of antioxidant like NAC to therapeutic regimen of terlipressin and albumin seems justifiable.[32
Failure to achieve sufficient increase in MAP with terlipressin is another important determinant of non-responder state.[5
] Achieving sufficient increase in MAP in these patients is quite challenging owing to the vascular non-reactivity induced by oxidant stress.[27
] Considering the possible role of oxidants in altering vascular reactivity to vasoconstrictors in HRS, use of antioxidants to improve vascular reactivity is thus favored.[27
] Short term use of terlipressin in HRS improves only circulatory dysfunction not renal function.[14
] On the other hand, long term use of terlipressin may be associated with improved responder rate.[33
] It is possible that long-term administration of vasoconstrictors may help in maintaining persistent and significant increase in MAP and there by maintain renal blood flow. Considering the lack of survival benefits with use of >4mg/d dose of terlipressin, prolonged treatment with low dose (<4mg/d) of terlipressin can thus be favored in non-responders for improving renal function. However considering the adverse effects of terlipressin, continuous monitoring for its cardiovascular adverse effects would become a major limitation for prolonged use. As NAC is found to prevent vasoconstricton related adverse effects of terlipressin, addition of NAC to long term regimen of terlipressin and albumin could also prove to be safe apart from synergistic in improving responder and survival rate.[34
] Considering the high cost of terlipressin, its long term use may not be practical. Noradrenaline, another vasoconstrictor drug that has relatively similar adverse reaction profile and beneficial effects as terlipressin in improving renal function and survival rate, could be promising cost effective alternative for terlipressin.[11
] Theoretically, noradrenaline has risk of decreasing blood flow to the liver.[12
] In addition, as the data on the causes of death in individual patients treated with noradrenaline is not available, it will be inconclusive to state whether it decreases or increase incidences of other causes of death.
Idea of overcoming the three major determinants of non-responder state by addition of antioxidants like NAC to long term regimen of terlipressin plus albumin may prove to be beneficial in improving renal function and survival in non-responders. With regard to improving survival benefits with increasing responder rate; uncertainty still remains over the success of achieving improved survival benefits. As patients who respond to vasoconstrictor therapy still die of HRS, impact of improving responder rate by improving vascular reactivity and severity of renal failure perse
needs to be studied further in randomized controlled trials. The significance of achieving survival benefits perhaps can also be blunted by the etiology of cirrhosis.[35
] Hence, apart from lack of survival benefits of terlipressin against other causes of death and possible increased incidences of deaths due to multi-organ failure, discrepancies in the survival rate and HRS reversal rate observed with terlipressin could also have been significantly influenced by the etiology of cirrhosis. Considering the complex interplay of the different factors influencing the survival rate; we are of the opinion that the true survival benefits of terlipressin cannot be estimated even if required sample size for its estimation is achieved. A study with patient characteristics favorable for higher survival or HRS reversal can record high survival benefits and vice-versa.
We must admit that our study has certain drawbacks. We have restricted our search to published studies in English. Our conclusion that the terlipressin has survival benefit only with respect to HRS alone as cause of death and not against other causes of death is dependent only on data from two randomized studies. With total population of only 158 patients analyzed from these two studies; sample size is very low to make such a conclusion. Since the data on individual causes of death in other randomized studies were not available, future reviews may come up with an acceptable conclusion if these data become available. Opinion that NAC can be beneficial in reversing non-responder state to responder state is supported by preliminary or observational studies not controlled studies is another drawback. As most of the eligible studies included patients of both types of HRS, considering the comparatively better prognosis associated with type 2 HRS, an influence of including these patients on the results of survival and HRS reversal benefits cannot be ruled out.