Urotensin II as a predictor for Hepato- renal syndrome in patients with liver Cirrhosis

1. Urotensin II as a predictor for Hepato- renal syndrome in patients with liver Cirrhosis By Reda M. El badawy Professor of Gastroenterology , Hepatology and Infectious Diseases. Banha University , Egypt

2. OMICS International 2nd International Conference on Hepatology 9-11 May 2016 Chicago, USA

3. Hepatorenal Syndrome(HRS) Definied as: Functional form of acute kidney injury(AKI) associated with advanced liver cirrhosis or fulminant hepatic failure (Wadei etal2013).

4. Types of HRS Type 1: the symptoms duration 2-4 weeks The patients has poor prognosis in(10%) and death occurred within 90 days unless liver transplantation planned . Type 2 : the symptoms >4 weeks Death occurred within 4-6 months and S.C ranged from 1.5-2mg/dl, once it is 2.5 mg/dl mean that GR<50%

5. Cont., Type 3: there is inapprant chronic renal dysfunction ( DM,GN….etc) Type 4: the symptoms associated with AFH

6. Could spontaneous recovery for HRS happen? Yes in a minorty of cases if liver functions imporoved quickly and very early diagnosis for HRS that occurred even before the development of ascites, and that our aim (pre HRS) .

7. The clinical characteristic , natural history and laboratory features of type 3 and 4 HRS have not been studied. This is according to the international Ascites Club(Salerno etal.,2007) and Santiago etal.,2008

8. Diagnosis of HRS Major Criteria : 1-patients with advanced hepatic failure acute or chronic and PH. 2- Doubling of S.Creatinine from basal line or >1.5mg/dL 3-proteinuria<500mg/dL with no evidance of parenchymal renal disease by urine analysis

9. 4-Exclude direct renal insult (shock, drugs..) 5-No sustained improvement in renal function after diuretic withdrawal and plasma volume expansion with IV albumin(1g/kg) to maximum of 100g N.B: This does not apply to patients who have interinsic renal disease plus CLD

10. Minor criteria of HRS 1-Urine volume <500 mL/24 h. 2-Urine sodium <10mEq/L. 3- Urine osmolarity > plasma osmolarity. 4-Urine blood cell <50 per high power field 5-Serum Sodium< 130 mEq/L According internationl ascites club 2007 minor criteria has eleminated as well as S.C level due to poor correlation with K.F.

11. Is it important to early diagnosis for HRS (pre HRS) ? Yes to avoid the high mortality that up to48%. A New concept and stratification of R.F is pre HRS ,this in patients with reduced renal blood flow but normal or slightly decrease GFR (Mindikoglu &Weir 2013)

12. HRS has a unique pathophysiological disorder that provides possibilities for studying the interplay between vasoconstrictor and vasodilator systems on the renal circulation . N.B :heamodynamic changes associated with endothelial shear stress occurred before the onset of ascites .

13. The development of HRS in people with cirrhosis portends a dismal(bad) prognosis because renal failure is usually irreversible unless liver transplantation is performed .

14. Pathophysiology of HRS In the early phases of portal hypertension(before Ascites), renal perfusion is maintained within normal or near-normal limits as the vasodilatory systems antagonize the renal effects of the vasoconstrictor systems (Underfilltheory ).

15. The alternative theory proposes that renal vasoconstriction in HRS is unrelated to systemic hemodynamics ( ascites) Evidence points to the vasodilatation theory as a more tangible explanation for the development of HRS(Ovetheoryrfill).

16. What about Urotensin II? Urotensin II (U II) is a somatostatin –like cyclic peptide, its vascular tone both species specific and diseases specific. It has dual action ,also autocrine and paracrine action.

17. Urotensin induce vasoconstriction through action on smooth muscle with different mediators activation e.g Ca,PLc,IP3 and Rho/-Kinase (Watanable etal.,2006) . Urotensin also induce vasodilation by action on endothelial cell with mediators like PGE,endothelin(ET),vasoactive intestinal peptides(VIP) and Nitrous Oxide(NO)

18. Urotension II and liver In patients with chronic liver disease, serum U II is elevated compared with controls. In addition, U II levels correlate with the severity of disease and with the extent of portal hypertension.

19. Finally, the baseline of U II levels can even carry a predictive value for determining survival or future portal hypertension complications like ascites , HRS,HE ….etc

20. Cont., Reduction in portal pressure with the use of U IIreceptor antagonist highlights a potenial mechanistic role of u 2 in the development and maintenance of portal hypertension (kemp etal.,2008).

21. Urotensin and body systems It is present all over body organs e.g Haert , Blood vessles , Lungs ,CNS…etc. The action on these organs depends on the balance between the vasoconstriction action by smooth muscle and vasodilatation by endothelial cell.

22. Interestingly , the vasodilatory effects of U II dominate over vasoconstriction in the portal circulation this is confirmed by the local overproduction of NO. This is important in maintaining portal blood flow and portal blood pressure(Kemp etal.,2008)

23. Aim of the study So the aim of this study was to evaluate the level and the role of Urotensin II in grades of liver diseases ( ascietic group and non ascietic group ) If U II can be used as predictor for diagnosis patients with early hepatorenal syndrome before ascites? .

24. Patients and Methods Fifty subjects 40patients with chronic liver diseases and 10 subjects apprently healthy selected from Gastroenterology, Hepatology and Infectious diseases Department, Benha University Hospital,Egypt.

25. The patients were divided into 3 groups: Group (1) 20 patients with ascites & Group (2)20 patients without ascites . Group (3) 10 Subjects as control. All matched as regards age and sex.

26. Selection of the patients Exclusion criteria: DM. Hypertensive patients and severe heart failure. Patients in bleeding at the time of taking blood sample or 3 days previously. Patients on diuretics for previous 3 days. Inclusion criteria: Patients with liver cirrhosis with and without ascites regardless the aetiology

27. Investigations All investigations done include:- CBC,LFT,s, FBS,kideny function tests(Urea &Creatinine) viral markers & US abdomen. Urotensin II level was measured by using immune diagnostic ELISA Kits (Cat. No. K 1013 – 110429) according to the manufacture's instructions

28. Statistical Methods The collected data were tabulated and analyzed using SPSS version 16 soft ware. Categorical data were presented as number and percentages while quantitative data were expressed as mean and standard deviation.

29. Urotensin II was presented as median and range using Mann Whitney test and Spearman's correlation coefficient for analysis. Chi square test (X2) and student “t” test were used as tests of significance for parametric data.

30. ROC curve was used to detect a cutoff value of urotensin II . P value <0.05 was considered ststistical significant.

31. ResultsTable (1): CBC among the studied groups

32. Table (2): Liver and Kidney profile among the studied groups.

33. Table (3): Ultrasonic findings of kidney among the studied groups.

34. Table (4): Spearman's correlation between urotensin II level and some studied variables.

35. Figure (1): Correlation between urotensin level (pg/ml) and urea level (mg/dl) in the two studied groups.

36. Fig. (2): ROC curve for accuracy and predictivity of urotensin in diagnosis of hepatorenal syndrome. sensitivity 66.7%, specificity 64.5% by ROC curve with PPV 35.3% and NPV 86.96% that was not statistical signficant.

37. Disscusion In decompensated cirrhotics, the probability of developing HRS with ascites ranges between 8-20% per year. This is increases to 40% at 5 years because HRS is fatal unless diagnosed early.

38. HRS diagnosis is one of exclusion , depends mainly on serum creatinine level, although it is a poor marker of renal function in patients with cirrhosis, no other validated and reliable noninvasive markers exist for monitoring renal function in these patients

39. A reduced GFR in the absence of other causes of renal failure in patients with chronic liver disease according to the criteria proposed by the International Ascites Club in 1996 is the gold standard for diagnosis of HRS.

40. Due to the difficulty in assessment of GFR in critically ill patients to daignose HRS and the limitations of serum creatinine as a measure of GFR an extensive search for a more sensitive laboratory marker of impaired renal function must be in carry out contionously .

41. Only a minority of patients with cirrhosis and elevated serum creatinine fulfills the criteria of hepatorenal syndrome . In a study done by (Jorg etal.,2002) U II level incresed in patients with HRS,but there was no correlation between U II and creatinine

42. Urotensin II as a Biomarker Altered plasma concentration of U 2 in diseases , such as heart failure,essential HTN, renal disease,DM and liver cirrhosis have raised the notion that U II may be a useful biomarker in detecting disease onset or progression (Jarolin ,2006 &Carmine etal., 2008).

43. In our study the results was A statistical significant positive association between serum U II and and blood urea level , P vaule(0.016) in patients without ascites. So according to the underfill theory of ascites formation this will be a good predictor to( detect) and early diagonsis of HRS that can be without ascites according to (Jarolin,2006)

44. What about Urea level Importance Urea synthesis by liver from amino acid through urea cycle by arginase and that is irriversable once it is formed must be excreted from the body . Urea excreted from blood by kideny in 75% of cases while in 25% by diffusion in tissue

45. The realization that U II can found as potent vasoconstrictive mediator in human as well as a broad range of other species may be of potential importance in the pathophysiology of liver cirrhosis (Liu et al.,2010)

46. The levelof U II was higher in ascietic patients compared to non ascietic and control but was not statistical significant that agree with (Romanelli etal.,2011) & disagree with (Kemp etal.,2007) The value was as follow : Ascites(5114-104490pg/l), no ascites (5227-71020) and control(5215-71000)

47. Protective effects of U II Although U II levsels are increased in many diseases compared physiological condition. This lead to better protection against adverse events than diseased individuals with lower U II levels e.g patients with stable cornory artery disease & patients with acute cardiac ischemia (Joyal etal.,2006)

48. In patients with ESRD, an inverse association was found between U II level and clinical outcome ( Zoccali etal.,2006). The possible mechanisms for the apparent protective role of U II in diseases include effect on volume overload and myocardial contractility,this would aid uremic patients (Russell etal.,2003& Carmine et 2008).

49. Recent studies revealed that myocardial dysfunction in cirrhotic patients has a role in the development of HRS or it is a preciptating factor (Mocarzel etal.,2015) Jack 2013 proved that U 2 is significantly inreased in subclinical HRS in LC patients

50. Potenial Theraputic Application There is a great deal of interest and research that focuses on the antagonism of the U2 –UT system e.g ., 1-Uranide Hu for hypertension(Zhu etal.,2006). 2-SB-657510 for atherosclerosis(Papadopoulos etal.,2009) 3-Palosuran (ACT-058362) for improvement of renal ischemia (Clozel etal.,2004),also reduce portal blood pressure(Trebicka etal.,2008)