- Email: [email protected]
Resistive Index and MELD-Na: Nephrologic Monitoring in Cirrhotic Patients Awaiting Liver Transplantation
Resistive Index and MELD-Na: Nephrologic Monitoring in Cirrhotic Patients Awaiting Liver Transplantation I. Umbro, F. Tinti, F. Fiacco, A. Zavatto, P. Piselli, V. Di Natale, S. Lai, A. Vitarelli, S. Ginanni Corradini, M. Rossi, L. Poli, P.B. Berloco, and A.P. Mitterhofer ABSTRACT Renal dysfunction in cirrhotic patients is primarily related to disturbances in circulatory function. In decompensated cirrhosis, ascites and water retention are associated with development of dilutional hyponatremia. The arterial resistive index (RI) is a measure of resistance to arterial flow within the renal vascular bed. Hyponatremia is an independent predictor of mortality in patients with ascites. The aim of this study was to evaluate intrarenal RI in end-stage liver disease (ESLD) patients awaiting liver transplantation (LT) and its association with renal and hepatic function as assessed by Model for End-Stage Liver Disease (MELD) and MELD-Na scores. We evaluated 40 cirrhotic patients (23 males, 17 females) awaiting LT from January 2009 to January 2012. Twenty-six of the 40 patients (65%) showed a renal RI 0.70, the normal value according to standard reported evaluations. Patients with RI 0.70 showed significantly higher MELD and MELD-Na scores as well as greater higher serum creatinine and lower serum sodium concentrations compared with subject displaying RI <0.70. The most relevant result of our study was the strong association between elevated renal RI in ESLD patients and advanced liver dysfunction, as demonstrated by MELD and MELD-Na scores, hyponatremia, ascites, and acute renal failure episodes. In conclusion, this study suggested that intrarenal RI assessment should be considered in the clinical and nephrologic monitoring of cirrhotic patients awaiting LT.
R
ENAL DYSFUNCTION in cirrhotic patients is primarily related to disturbances in circulatory function characterized by reduced systemic vascular resistance due to arterial vasodilatation in the splanchnic circulation triggered by portal hypertension.1e4 In advanced cirrhosis, arterial pressure can be maintained through the activation of vasoconstrictor systems, including the renin-angiotensin system, the sympathetic nervous system, and nonosmotic hypersecretion of antidiuretic hormone (ADH), with important impacts on kidney function, causing intrarenal vasoconstriction and hypoperfusion.2,3 In this scenario, ascites and water retention are associated with subsequent increases in total body water with development of dilutional hyponatremia.5 Approximately 30% of patients with cirrhosis and ascites display hyponatremia (serum sodium <130 mEq/L).6 Hyponatremia in cirrhosis highlights the marked circulatory dysfunction that suggests advanced liver disease and is associated with high morbidity and mortality rates.7 Indeed, once the important circulatory dysfunction induced by
hepatic failure is removed, after liver transplantation, serum sodium levels improve rapidly.8,9 The resistive index (RI) is a measure of resistance to arterial flow within the renal vascular bed.10,11 It is the most widely used index for this estimation. Intrarenal arterial impedance can be easily and noninvasively assessed by
From the Department of Clinical Medicine, Nephrology and Dialysis Unit (I.U., F.T., F.F., A.Z., V.D.N., S.L., A.P.M.); Department of Epidemiology and Preclinical Research, IRCCS L Spallanzani (P.P.); Department of Cardiovascular and Respiratory Science (A.V.); Gastroenterology Unit, Department of Clinical Medicine (S.G.C.); and Organ Transplant Unit “Paride Stefanini”, and Department of General Surgery (L.P., M.R., P.B.B.). I Faculty of Medicine and Surgery, Sapienza University of Rome, Rome, Italy. Supported by the Consorzio Interuniversitario per i Trapianti. Address reprint requests to Anna Paola Mitterhofer, Viale dell’ Università 37, 00185 Rome, Italy. E-mail: annapaola.mitter@ uniroma1.it
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.07.040
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2676
Transplantation Proceedings, 45, 2676e2679 (2013)
RESISTIVE INDEX AND MELD-Na
measuring the pulsatility index or RI with real-time color Doppler ultrasonography.12 A resistive index <0.70 is considered to be a normal value, according to standard reports.13,14 An elevated RI (0.70) has been shown to be a reliable indicator of high renal vascular resistance in a variety of pathologic conditions, such as kidney obstruction,13 acute tubular necrosis,11 renal vein thrombosis,15 and hemolytic-uremic syndrome.14 Indeed high renal RI is present in w50% of nonazotemic cirrhotic patients with ascites due to increased resistance in the intrarenal arterial bed.16,17 RI is significantly higher among patients with kidney failure, correlating significantly with elevated plasma renin activity and plasma aldosterone levels.18e20 Cirrhotic patients with abnormal RI and normal renal function at baseline seem to be at greater risk for subsequent development of functional renal failure21e23 and hepatorenal syndrome.24,25 Therefore, high renal RI may be associated with a greater risk of renal dysfunction,22 as demonstrated by a decrease in RI to normal within 2 months after liver transplantation (LT).26 Renal RI shows progressively increasing levels with worsening of liver disease, deterioration of renal function, and activation of endogenous vasoactive systems.19 The Model for End-Stage Liver Disease (MELD) score is a predictor of survival in cirrhotic patients awaiting LT. It consists of serum bilirubin, and serum creatinine (sCr) concentrations as well as international normalized ratio (INR).27 In a previous study, we showed a tight association between liver dysfunction as evaluated by MELD score and the occurrence of renal failure after LT that adversely affected patient survival.28 The MELD score may not accurately reflect the risk of death in patients with hyponatremia.29e32 Considerable evidence suggests that addition of serum sodium concentration to the MELD score better identifies patients in greatest need of LT; it improves the prediction of waiting list mortality.33 Other recent studies have shown that hyponatremia is an independent predictor of mortality in patients with ascites due to portal hypertension.34 It is significantly associated with increased severity of liver disease as assessed by MELD score and risk of spontaneous bacterial peritonitis, hepatic hydrothorax, and risk for hepatic encephalopathy.35e37 Therefore, the MELD-Na score has recently been proposed for patients with serum sodium concentrations reduced to values from l25 to 140 mmol/L.31,32,38,39 We sought to evaluate intrarenal RI in ESLD patients awaiting LT and its association with renal and hepatic function as evaluated by MELD and MELD-Na score. MATERIALS AND METHODS This retrospective single-center study included prospectively collected data on 40 cirrhotic patients namely 23 men and 17 women median age 57 years (interquartile range [IQR], 52-61), awaiting LT from January 2009 to January 2012. Clinical data included patient age and sex, cirrhosis etiology, hepatitis C (HCV) or B (HBV) infection, hepatocarcinoma, transjugular intrahepatic
2677 Table 1. Clinical Characteristics and Parameters of Renal and Hepatic Function in 40 Cirrhotic Patients at the Time of Listing for Liver Transplantation Age (y) Male Etiology Alcoholic cirrhosis Viral cirrhosis Other HCV infection HBV infection Hepatocarcinoma Ascites TIPS Diabetes mellitus Hypertension MELD score sCr (mg/dL) GFR (mL/min) BUN (mg/(dL) Albumin (mg/dL) Bilirubin (mg/dL) INR CRF pre-LT
57 (52e61) 23 (57.5%) 16 16 8 12 8 8 18 9 18 11 15 0.88 90.3 17.5 3.0 2.17 1.35 8
(40%) (40%) (20%) (30%) (20%) (20%) (45%) (22.5%) (45%) (27.5%) (11e20) (0.70e1.10) (59.9e110.0) (13.5e23.0) (2.6e3.6) (1.39e4.23) (1.19e1.44) (20%)
Values are presented as median (interquartile range) or n(%); HCV, hepatitis C virus; HBV, hepatitis B virus; TIPS, transjugular intrahepatic portosystemic shunt; MELD, Model for End-Stage Liver Disease; Na, serum sodium; sCr, serum creatinine; GFR, glomerular filtration rate (estimated by Modification of Diet in Renal Disease formula); BUN, blood urea nitrogen; INR, international normalized ratio; CRF, chronic renal failure; LT, liver transplantation.
portosystemic shunt ascites, diabetes mellitus, or hypertension (Table 1). Patients clinically evaluated at the time of listing were reexamined every 3 months for 1 year thereafter, considering history, physical examination, and diagnostic tests. Every 3 months we collected retrospective monthly data on sCr, glomerular filtration rate (GFR) as estimated by the simplified Modification of Diet in Renal Disease (MDRD) formula, blood urea nitrogen (BUN), serum sodium, albumin, bilirubin, and INR to calculate MELD and MELD-Na scores. Acute renal failure (ARF) was defined and classified on the basis of Acute Kidney Injury Network (AKIN) criteria.40 Chronic renal failure (CRF) was defined as a GFR <60 mL/min/1.73 m2 as evaluated with the MDRD formula for >3 months, regardless of the presence or absence of structural kidney damage, as proposed by the Working Party proposal for cirrhotic patients and according to the practice guidelines from the Kidney Disease Outcomes Quality Initiatives Workgroup.41 All patients were evaluated with renal Doppler ultrasonography. RI 0.70 was defined as abnormal.13,14 Patients were divided into 2 groups according to intrarenal RI values: RI 0.70 and RI < 0.70.
Technical Information Ultrasound measurements were performed with the use of a Toshiba Aplio XV 2.5e5.0 MHz convex probe with a 100Hz cutoff filter and <60 angle of insonation. The subjects fasted overnight and rested in the supine position in bed for 10 minutes before the ultrasound measurements. Intrarenal arteries (RAs), either interlobar or segmental branches were evaluated by color Doppler ultrasound. Three Doppler waveform tracings were obtained from each kidney by sampling the RA: right (RRA-RA) and left (LRARA) in the superior, middle, and inferior portions of each kidney.
2678
UMBRO, TINTI, FIACCO ET AL
The mean values of each kidney’s parameters were obtained from measurements of waveforms of both right and left renal areas. Subjects were instructed to hold their breath during the Doppler flow spectrum imaging. Based on a clear spectrum image, peak systolic velocity (PSV) and end-diastolic velocity (EDV) of the main renal artery, interlobar artery, and interlobular artery were measured to calculate the RI for each vessel as (PSV EDV)/PSV. Images from 3 successive cardiac cycles were obtained to calculate the mean RI. Renal Doppler ultrasonography was interpreted by 1 investigator according to a standard protocol.
Statistical Technique Data are presented as median and IQR for continuous variables and as frequency and percentage for categoric variables. Comparison between patients with normal versus elevated RI was done with Mann-Whitney U tests continuous variables (ie, MELD score, MELD-Na score, sCr, and serum sodium) or chi-square tests (or Fisher exact test when applicable) for categoric variables, ie, ascites and ARF. All tests were performed using SPSS 20.0 (SPSS, Chicago, Illinois) with P < .05 consisted to be significant.
RESULTS
Twenty-six among 40 patients (65%) showed a renal RI 0.70. Among them, 16/2 (61%) developed ARF versus 3/14 (21%) with RI < 0.70 (P ¼ .041). Patients with RI 0.70 showed significantly higher MELD and MELD-Na score, as well as greater sCr and lower serum sodium concentrations compared with patients with RI < 0.70 (P values .008, .001, .005, and .003, respectively). Moreover, we observed an association between RI 0.70 and the presence of ascites and occurrence of ARF (P value.008, and .041, respectively; Table 2.) DISCUSSION
Low serum sodium concentrations in ESLD seem to be associated with the severity of circulatory failure associated with advanced cirrhosis. In these cases, hyponatremia is related to a nonosmotic hypersecretion of ADH, which in turn depends on the degree of impairment in circulatory function.3,5 Intrarenal RI, a noninvasive measure of resistance to arterial flow within the renal vascular bed,10,11 shows the presence of renal vasoconstriction often before changes in sCr concentrations.42e44 About 50% of nonazotemic Table 2. Results of Renal and Hepatic Parameters Evaluated in Patients With Rl < 0.70 (14/40) and Rl ‡ 0.70 (26/40) Rl < 0.70
Rl 0.70
MELD score 12.00 (10.00e14.50) 17.00 (12.75e21.25) MELD-Na score 13.49 (11.37e15.03) 18.10 (14.40e22.37) Serum creatinine 0.90 (0.75e1.03) 1.30 (0.97e1.72) Serum sodium 136 (135e137) 133 (131e136) Ascites 2/14 (14%) 16/26 (61%) ARF 3/14 (21%) 16/26 (61%)
P Value
.008 .001 .005 .003 .008 .041
Values are presented as median (interquartite range) or n (%). RI, resistive index; MELD, Model for End-Stage Liver Disease; Na, serum sodium; ARF, acute renal failure.
cirrhotic patients with ascites show an elevated RI, (0.70) due to increased resistance in the intrarenal arterial bed.16,17 Cirrhotic patients with abnormal RI and normal renal function at baseline are at greater risk for subsequent development of functional renal failure11,21,23 and hepatorenal syndrome.24,25 Therefore high renal RI is associated with a greater risk of renal dysfunction and dialysis after transplantation.22 In the present study, we evaluated RI in cirrhotic patients awaiting LT in relation to renal and hepatic function. Our results showed a significant association between after high RI (0.70) and the MELD score, MELD-Na score, sCr, and hyponatremia. Hyponatremia, in particular, is a common condition in cirrhotic patients with refractory ascites associated with advanced liver disease, episodes of ARF, and increased mortality.41,45,46 This study showed that elevated renal RI in ESLD patients highlights the renal condition and advanced liver dysfunction, generally associated with hyponatremia that is probably dilutional due to ADH hypersecretion In conclusion, this study suggests that intrarenal RI assessment should be considered for clinical and nephrologic monitoring of cirrhotic patients awaiting LT particularly those with normal renal function. REFERENCES 1. Ginès P, Cárdenas A, Schrier RW. Liver disease and the kidney. In: Schrier RW, ed. Diseases of the kidney and urinary tract. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:2179e2205. 2. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8:1151e1157. 3. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology. 1996;23:164e176. 4. Martin PY, Ginès P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339:533e541. 5. Ginès P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology. 1998;28(3):851e864. 6. Arroyo V, Rodés J, Gutierrez Lizarraga MA, et al. Prognostic value of spontaneous hyponatremia in cirrhosis with ascites. Am J Dig Dis. 1976;21:249e256. 7. Bengus A, Babiuc RD. Hyponatremiadpredictor of adverse prognosis in cirrhosis. J Med Life. 2012;5(2):176e178. 8. Abbasoglu O, Goldstein RM, Vodpally MS, et al. Liver transplantation in hyponatremia patients with emphasis on central pontine myelinolysis. Clin Transplant. 1998;12:263e269. 9. Wszolek ZK, McComb RD, Pfeiffer RF, et al. Pontine and extrapontine myelinolysis following liver transplantation. Relationship to serum sodium. Transplantation. 1989;48:1006e1012. 10. Platt JF, Ellis JH, Rubin JM, et al. Intrarenal arterial Doppler sonography in patients with nonobstructive renal disease: correlation of resistive index with biopsy findings. Am J Roentgenol. 1990;154:1223e1227. 11. Platt JF, Rubin JM, Ellis JH. Acute renal failure: possible role of duplex Doppler US in distinction between acute prerenal failure and acute tubular necrosis. Radiology. 1991;179:419e423. 12. Norris CS, Barnes RW. Renal artery flow velocity analysis: a sensitive measure of experimental and clinical renovascular resistance. J Surg Res. 1984;36:230e236. 13. Platt JF, Rubin JM, Ellis JH. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography. Am J Roentgenol. 1989;153:997e1000.
RESISTIVE INDEX AND MELD-Na 14. Patriquin HB, O’Regan S, Robitaille P, et al. Hemolytic uremic syndrome: intrarenal arterial Doppler patterns as a useful guide to therapy. Radiology. 1989;172:625e628. 15. Parvey HR, Eisenberg RL. Image-directed Doppler sonography of the intrarenal arteries in acute renal vein thrombosis. J Clin Ultrasound. 1990;18:512e516. 16. Colli A, Cocciolo M, Riva C, et al. Abnormal renovascular impedance in patients with hepatic cirrhosis: detection with duplex US. Radiology. 1993;187:561e563. 17. Sacerdoti D, Bolognesi M, Merkel C, et al. Renal vasoconstriction in cirrhosis evaluated by duplex-Doppler ultrasonography. Hepatology. 1993;17:219e224. 18. Maroto A, Ginès A, Saló J, et al. Diagnosis of functional kidney failure of cirrhosis with Doppler sonography: prognostic value of resistive index. Hepatology. 1994;20:839e844. 19. Rendón Unceta P, Macìas Rodrìguez MA, et al. Renal Doppler ultrasonography and its relationship with the renal function in patients with liver cirrhosis. Med Clin (Bare). 2001;116(15): 561e564. 20. Koda M, Murawaki Y, Kawasaki H. Renovascular resistance assessed by color Doppler ultrasonography in patients with chronic liver diseases. J Gastroenterol Hepatol. 2000;15(12):1424e1429. 21. Arroyo V, Ginés P, Navasa M, et al. Renal failure in cirrhosis and liver transplantation. Transplant Proc. 1993;25:1734e1739. 22. Platt JF, Ellis JH, Rubin JM, et al. Renal duplex-Doppler ultrasonography: noninvasive predictor of kidney dysfunction and hepatorenal failure in liver disease. Hepatology. 1994;20:362e369. 23. Celebi H, Donder E, Celiker H. Renal blood flow detection with Doppler ultrasonography in patients with hepatic cirrhosis. Arch Intern Med. 1997;157:564e566. 24. Gentilini P, Laffi G. Renal functional impairment and sodium retention in liver cirrhosis. Digestion. 1989;43:1e3. 25. Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis. Am J Med. 1987;82:945e952. 26. Platt JF, Marn CS, Baliga PK, et al. Renal dysfunction in hepatic disease: early identification with renal duplex Doppler US in patients who undergo liver transplantation. Radiology. 1992;183(3):801e806. 27. Kamath PS, Kim WR. The Model for End-Stage Liver Disease (MELD). Hepatology. 2007;45:797e805. 28. Umbro I, Tinti F, Mordenti M, et al. Model for End-Stage Liver Disease score versus Simplified Acute Physiology Score criteria in acute renal failure after liver transplantation. Transplant Proc. 2011;43(4):1139e1141. 29. Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl. 2005;11:336e343. 30. Heuman DM, Abou-Assi SG, Habib A, et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology. 2004;40:802e810.
2679 31. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology. 2005;41:32e39. 32. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology. 2006;130:1652e1660. 33. Gaglio P, Marfo K, Chiodo 3rd J. Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin v(2)receptor antagonist tolvaptan. Dig Dis Sci. 2012;57(11):2774e2785. 34. Planas R, Montoliu S, Ballesté B, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4:1386e1394. 35. Kim JH, Lee JS, Lee SH, et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med. 2009;24:106e112. 36. Guevara M, Baccaro ME, Torre A, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol. 2009;104:1382e1389. 37. Guevara M, Baccaro ME, Rios J, et al. Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration. Liver Int. 2010;30:1137e1142. 38. Biggins SW, Bambha K. MELD-based liver allocation: who is underserved? Semin Liver Dis. 2006;26:211e220. 39. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018e1026. 40. Wong F, Nadim MK, Kellum JA, et al. Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut. 2011;60:702e709. 41. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39: Sl-266. 42. Epstein M, Berk DP, Hollenberg NK, et al. Renal failure in the patient with cirrhosis the role of active vasoconstriction. Am J Med. 1970;49:175e185. 43. Arroyo V, Ginés P, Jimenez W, et al. Ascites, renal failure, and electrolyte disorders in cirrhosis: Pathogenesis, diagnosis and treatment. In: Mclntyre N, Benhamou JP, Bircher J, eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford Medical Publications; 1991:429. 44. Schrier RW, Niederberger M, Weigert A, Gines P. Peripheral arterial vasodilatation: determinant of functional spectrum of cirrhosis. Semin Liver Dis. 1994;14:14e22. 45. Llach J, Ginés P, Arroyo V, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology. 1988;94:482e487. 46. Fernandez-Esparrach G, Sanchez-Fueyo A, Ginés P, et al. A prognostic model for predicting survival in cirrhosis with ascites. J Hepatol. 2001;34:46e52.
R
ENAL DYSFUNCTION in cirrhotic patients is primarily related to disturbances in circulatory function characterized by reduced systemic vascular resistance due to arterial vasodilatation in the splanchnic circulation triggered by portal hypertension.1e4 In advanced cirrhosis, arterial pressure can be maintained through the activation of vasoconstrictor systems, including the renin-angiotensin system, the sympathetic nervous system, and nonosmotic hypersecretion of antidiuretic hormone (ADH), with important impacts on kidney function, causing intrarenal vasoconstriction and hypoperfusion.2,3 In this scenario, ascites and water retention are associated with subsequent increases in total body water with development of dilutional hyponatremia.5 Approximately 30% of patients with cirrhosis and ascites display hyponatremia (serum sodium <130 mEq/L).6 Hyponatremia in cirrhosis highlights the marked circulatory dysfunction that suggests advanced liver disease and is associated with high morbidity and mortality rates.7 Indeed, once the important circulatory dysfunction induced by
hepatic failure is removed, after liver transplantation, serum sodium levels improve rapidly.8,9 The resistive index (RI) is a measure of resistance to arterial flow within the renal vascular bed.10,11 It is the most widely used index for this estimation. Intrarenal arterial impedance can be easily and noninvasively assessed by
From the Department of Clinical Medicine, Nephrology and Dialysis Unit (I.U., F.T., F.F., A.Z., V.D.N., S.L., A.P.M.); Department of Epidemiology and Preclinical Research, IRCCS L Spallanzani (P.P.); Department of Cardiovascular and Respiratory Science (A.V.); Gastroenterology Unit, Department of Clinical Medicine (S.G.C.); and Organ Transplant Unit “Paride Stefanini”, and Department of General Surgery (L.P., M.R., P.B.B.). I Faculty of Medicine and Surgery, Sapienza University of Rome, Rome, Italy. Supported by the Consorzio Interuniversitario per i Trapianti. Address reprint requests to Anna Paola Mitterhofer, Viale dell’ Università 37, 00185 Rome, Italy. E-mail: annapaola.mitter@ uniroma1.it
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.07.040
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2676
Transplantation Proceedings, 45, 2676e2679 (2013)
RESISTIVE INDEX AND MELD-Na
measuring the pulsatility index or RI with real-time color Doppler ultrasonography.12 A resistive index <0.70 is considered to be a normal value, according to standard reports.13,14 An elevated RI (0.70) has been shown to be a reliable indicator of high renal vascular resistance in a variety of pathologic conditions, such as kidney obstruction,13 acute tubular necrosis,11 renal vein thrombosis,15 and hemolytic-uremic syndrome.14 Indeed high renal RI is present in w50% of nonazotemic cirrhotic patients with ascites due to increased resistance in the intrarenal arterial bed.16,17 RI is significantly higher among patients with kidney failure, correlating significantly with elevated plasma renin activity and plasma aldosterone levels.18e20 Cirrhotic patients with abnormal RI and normal renal function at baseline seem to be at greater risk for subsequent development of functional renal failure21e23 and hepatorenal syndrome.24,25 Therefore, high renal RI may be associated with a greater risk of renal dysfunction,22 as demonstrated by a decrease in RI to normal within 2 months after liver transplantation (LT).26 Renal RI shows progressively increasing levels with worsening of liver disease, deterioration of renal function, and activation of endogenous vasoactive systems.19 The Model for End-Stage Liver Disease (MELD) score is a predictor of survival in cirrhotic patients awaiting LT. It consists of serum bilirubin, and serum creatinine (sCr) concentrations as well as international normalized ratio (INR).27 In a previous study, we showed a tight association between liver dysfunction as evaluated by MELD score and the occurrence of renal failure after LT that adversely affected patient survival.28 The MELD score may not accurately reflect the risk of death in patients with hyponatremia.29e32 Considerable evidence suggests that addition of serum sodium concentration to the MELD score better identifies patients in greatest need of LT; it improves the prediction of waiting list mortality.33 Other recent studies have shown that hyponatremia is an independent predictor of mortality in patients with ascites due to portal hypertension.34 It is significantly associated with increased severity of liver disease as assessed by MELD score and risk of spontaneous bacterial peritonitis, hepatic hydrothorax, and risk for hepatic encephalopathy.35e37 Therefore, the MELD-Na score has recently been proposed for patients with serum sodium concentrations reduced to values from l25 to 140 mmol/L.31,32,38,39 We sought to evaluate intrarenal RI in ESLD patients awaiting LT and its association with renal and hepatic function as evaluated by MELD and MELD-Na score. MATERIALS AND METHODS This retrospective single-center study included prospectively collected data on 40 cirrhotic patients namely 23 men and 17 women median age 57 years (interquartile range [IQR], 52-61), awaiting LT from January 2009 to January 2012. Clinical data included patient age and sex, cirrhosis etiology, hepatitis C (HCV) or B (HBV) infection, hepatocarcinoma, transjugular intrahepatic
2677 Table 1. Clinical Characteristics and Parameters of Renal and Hepatic Function in 40 Cirrhotic Patients at the Time of Listing for Liver Transplantation Age (y) Male Etiology Alcoholic cirrhosis Viral cirrhosis Other HCV infection HBV infection Hepatocarcinoma Ascites TIPS Diabetes mellitus Hypertension MELD score sCr (mg/dL) GFR (mL/min) BUN (mg/(dL) Albumin (mg/dL) Bilirubin (mg/dL) INR CRF pre-LT
57 (52e61) 23 (57.5%) 16 16 8 12 8 8 18 9 18 11 15 0.88 90.3 17.5 3.0 2.17 1.35 8
(40%) (40%) (20%) (30%) (20%) (20%) (45%) (22.5%) (45%) (27.5%) (11e20) (0.70e1.10) (59.9e110.0) (13.5e23.0) (2.6e3.6) (1.39e4.23) (1.19e1.44) (20%)
Values are presented as median (interquartile range) or n(%); HCV, hepatitis C virus; HBV, hepatitis B virus; TIPS, transjugular intrahepatic portosystemic shunt; MELD, Model for End-Stage Liver Disease; Na, serum sodium; sCr, serum creatinine; GFR, glomerular filtration rate (estimated by Modification of Diet in Renal Disease formula); BUN, blood urea nitrogen; INR, international normalized ratio; CRF, chronic renal failure; LT, liver transplantation.
portosystemic shunt ascites, diabetes mellitus, or hypertension (Table 1). Patients clinically evaluated at the time of listing were reexamined every 3 months for 1 year thereafter, considering history, physical examination, and diagnostic tests. Every 3 months we collected retrospective monthly data on sCr, glomerular filtration rate (GFR) as estimated by the simplified Modification of Diet in Renal Disease (MDRD) formula, blood urea nitrogen (BUN), serum sodium, albumin, bilirubin, and INR to calculate MELD and MELD-Na scores. Acute renal failure (ARF) was defined and classified on the basis of Acute Kidney Injury Network (AKIN) criteria.40 Chronic renal failure (CRF) was defined as a GFR <60 mL/min/1.73 m2 as evaluated with the MDRD formula for >3 months, regardless of the presence or absence of structural kidney damage, as proposed by the Working Party proposal for cirrhotic patients and according to the practice guidelines from the Kidney Disease Outcomes Quality Initiatives Workgroup.41 All patients were evaluated with renal Doppler ultrasonography. RI 0.70 was defined as abnormal.13,14 Patients were divided into 2 groups according to intrarenal RI values: RI 0.70 and RI < 0.70.
Technical Information Ultrasound measurements were performed with the use of a Toshiba Aplio XV 2.5e5.0 MHz convex probe with a 100Hz cutoff filter and <60 angle of insonation. The subjects fasted overnight and rested in the supine position in bed for 10 minutes before the ultrasound measurements. Intrarenal arteries (RAs), either interlobar or segmental branches were evaluated by color Doppler ultrasound. Three Doppler waveform tracings were obtained from each kidney by sampling the RA: right (RRA-RA) and left (LRARA) in the superior, middle, and inferior portions of each kidney.
2678
UMBRO, TINTI, FIACCO ET AL
The mean values of each kidney’s parameters were obtained from measurements of waveforms of both right and left renal areas. Subjects were instructed to hold their breath during the Doppler flow spectrum imaging. Based on a clear spectrum image, peak systolic velocity (PSV) and end-diastolic velocity (EDV) of the main renal artery, interlobar artery, and interlobular artery were measured to calculate the RI for each vessel as (PSV EDV)/PSV. Images from 3 successive cardiac cycles were obtained to calculate the mean RI. Renal Doppler ultrasonography was interpreted by 1 investigator according to a standard protocol.
Statistical Technique Data are presented as median and IQR for continuous variables and as frequency and percentage for categoric variables. Comparison between patients with normal versus elevated RI was done with Mann-Whitney U tests continuous variables (ie, MELD score, MELD-Na score, sCr, and serum sodium) or chi-square tests (or Fisher exact test when applicable) for categoric variables, ie, ascites and ARF. All tests were performed using SPSS 20.0 (SPSS, Chicago, Illinois) with P < .05 consisted to be significant.
RESULTS
Twenty-six among 40 patients (65%) showed a renal RI 0.70. Among them, 16/2 (61%) developed ARF versus 3/14 (21%) with RI < 0.70 (P ¼ .041). Patients with RI 0.70 showed significantly higher MELD and MELD-Na score, as well as greater sCr and lower serum sodium concentrations compared with patients with RI < 0.70 (P values .008, .001, .005, and .003, respectively). Moreover, we observed an association between RI 0.70 and the presence of ascites and occurrence of ARF (P value.008, and .041, respectively; Table 2.) DISCUSSION
Low serum sodium concentrations in ESLD seem to be associated with the severity of circulatory failure associated with advanced cirrhosis. In these cases, hyponatremia is related to a nonosmotic hypersecretion of ADH, which in turn depends on the degree of impairment in circulatory function.3,5 Intrarenal RI, a noninvasive measure of resistance to arterial flow within the renal vascular bed,10,11 shows the presence of renal vasoconstriction often before changes in sCr concentrations.42e44 About 50% of nonazotemic Table 2. Results of Renal and Hepatic Parameters Evaluated in Patients With Rl < 0.70 (14/40) and Rl ‡ 0.70 (26/40) Rl < 0.70
Rl 0.70
MELD score 12.00 (10.00e14.50) 17.00 (12.75e21.25) MELD-Na score 13.49 (11.37e15.03) 18.10 (14.40e22.37) Serum creatinine 0.90 (0.75e1.03) 1.30 (0.97e1.72) Serum sodium 136 (135e137) 133 (131e136) Ascites 2/14 (14%) 16/26 (61%) ARF 3/14 (21%) 16/26 (61%)
P Value
.008 .001 .005 .003 .008 .041
Values are presented as median (interquartite range) or n (%). RI, resistive index; MELD, Model for End-Stage Liver Disease; Na, serum sodium; ARF, acute renal failure.
cirrhotic patients with ascites show an elevated RI, (0.70) due to increased resistance in the intrarenal arterial bed.16,17 Cirrhotic patients with abnormal RI and normal renal function at baseline are at greater risk for subsequent development of functional renal failure11,21,23 and hepatorenal syndrome.24,25 Therefore high renal RI is associated with a greater risk of renal dysfunction and dialysis after transplantation.22 In the present study, we evaluated RI in cirrhotic patients awaiting LT in relation to renal and hepatic function. Our results showed a significant association between after high RI (0.70) and the MELD score, MELD-Na score, sCr, and hyponatremia. Hyponatremia, in particular, is a common condition in cirrhotic patients with refractory ascites associated with advanced liver disease, episodes of ARF, and increased mortality.41,45,46 This study showed that elevated renal RI in ESLD patients highlights the renal condition and advanced liver dysfunction, generally associated with hyponatremia that is probably dilutional due to ADH hypersecretion In conclusion, this study suggests that intrarenal RI assessment should be considered for clinical and nephrologic monitoring of cirrhotic patients awaiting LT particularly those with normal renal function. REFERENCES 1. Ginès P, Cárdenas A, Schrier RW. Liver disease and the kidney. In: Schrier RW, ed. Diseases of the kidney and urinary tract. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:2179e2205. 2. Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilatation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8:1151e1157. 3. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology. 1996;23:164e176. 4. Martin PY, Ginès P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med. 1998;339:533e541. 5. Ginès P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology. 1998;28(3):851e864. 6. Arroyo V, Rodés J, Gutierrez Lizarraga MA, et al. Prognostic value of spontaneous hyponatremia in cirrhosis with ascites. Am J Dig Dis. 1976;21:249e256. 7. Bengus A, Babiuc RD. Hyponatremiadpredictor of adverse prognosis in cirrhosis. J Med Life. 2012;5(2):176e178. 8. Abbasoglu O, Goldstein RM, Vodpally MS, et al. Liver transplantation in hyponatremia patients with emphasis on central pontine myelinolysis. Clin Transplant. 1998;12:263e269. 9. Wszolek ZK, McComb RD, Pfeiffer RF, et al. Pontine and extrapontine myelinolysis following liver transplantation. Relationship to serum sodium. Transplantation. 1989;48:1006e1012. 10. Platt JF, Ellis JH, Rubin JM, et al. Intrarenal arterial Doppler sonography in patients with nonobstructive renal disease: correlation of resistive index with biopsy findings. Am J Roentgenol. 1990;154:1223e1227. 11. Platt JF, Rubin JM, Ellis JH. Acute renal failure: possible role of duplex Doppler US in distinction between acute prerenal failure and acute tubular necrosis. Radiology. 1991;179:419e423. 12. Norris CS, Barnes RW. Renal artery flow velocity analysis: a sensitive measure of experimental and clinical renovascular resistance. J Surg Res. 1984;36:230e236. 13. Platt JF, Rubin JM, Ellis JH. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography. Am J Roentgenol. 1989;153:997e1000.
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