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Liver Stiffness is Reduced to Normal After Successful Renal Transplantation: A Prospective Cohort Study

      Background

      Liver stiffness (LS) may be falsely elevated in patients on maintenance hemodialysis (MHD) due to fluid overload. We measured LS change by transient elastography (TE) in MHD patients before and after successful renal transplantation.

      Method

      Adults on ≥2 years of MHD, without additional risk factors for liver fibrosis or fluid overload, and planned for renal transplantation were prospectively recruited. LS was measured on two occasions, i.e., within two weeks before transplantation (pre-Tx LS) and after ≥ 3 months after successful transplantation (post-Tx LS). The participants with pre-Tx LS ≤ 7.0 KPa and >7.0 KPa were classified as “Group I” and “Group II,” respectively. Categorical and numerical data are expressed as ratio/proportions and mean (SD), respectively.

      Results

      Paired data from 43 participants (males 42 [97.7%]; age 32 [11] years) were analyzed. The pre-Tx and post-Tx LS of the entire cohort, measured at 307 (198) days of interval, were 8.5 (7.3) KPa and 6.7 (3.1) KPa, respectively. Before transplantation, 21 (49%) participants belonged to Group II and 22 (51%) to Group I. Among the Group II participants, 12 (57%) showed LS normalization after 312 (182) days of transplantation. Of the 22 participants in Group I, three (13.6%) showed LS elevation to >7.0 KPa after 303 (217) days of transplantation. The mean LS changes among the overall cohort, Group II, and Group I were −1.8 KPa, −4.1 KPa, and +0.2 KPa, respectively.

      Conclusion

      LS in people on MHD may be falsely elevated, which is likely to normalize after successful renal transplantation.

      Keywords

      Abbreviations:

      ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), CKD (Chronic kidney disease), HCV (Hepatitis C virus), MHD (Maintenance hemodialysis), TE (Transient elastography), LS (Liver stiffness)
      Patients with significant liver fibrosis have reduced liver function
      • Tsochatzis E.A.
      • Bosch J.
      • Burroughs A.K.
      Liver cirrhosis.
      and are at high risk for prolonged hospital stay, postoperative complications, and death following any major surgery such as organ transplantation.
      • O'Leary J.G.
      • Yachimski P.S.
      • Friedman L.S.
      Surgery in the patient with liver disease.
      People on maintenance hemodialysis (MHD) have a high prevalence of hepatitis C virus (HCV) infection
      • Goel A.
      • Seguy N.
      • Aggarwal R.
      Burden of hepatitis C virus infection in India: a systematic review and meta-analysis.
      and high risk for the progression of liver fibrosis than those with normal renal function.
      • Espinosa M.
      • Martin-Malo A.
      • Alvarez de Lara M.A.
      • et al.
      Risk of death and liver cirrhosis in anti-HCV-positive long-term haemodialysis patients.
      All those with suspected liver disease need evaluation for the severity of liver fibrosis before renal transplantation.
      Liver biopsy, the gold standard for the assessment of liver fibrosis, is largely replaced by non-invasive methods of fibrosis assessment.
      • Rockey D.C.
      • Caldwell S.H.
      • Goodman Z.D.
      • et al.
      Liver biopsy.
      Such non-invasive methods include blood tests, radiological evaluation, or elastography.
      EASL-ALEH Clinical Practice Guidelines
      Non-invasive tests for evaluation of liver disease severity and prognosis.
      Transient elastography (TE) is one of the most contemporary non-invasive techniques for fibrosis assessment. The TE measures the liver stiffness (LS) as a surrogate marker of liver fibrosis, and the stiffness is expressed in KiloPascal (KPa). The LS may also be increased by several non-hepatic factors such as post-prandial state,
      • Alvarez D.
      • Orozco F.
      • Mella J.M.
      • et al.
      Meal ingestion markedly increases liver stiffness suggesting the need for liver stiffness determination in fasting conditions.
      acute inflammation in the liver,
      • Arena U.
      • Vizzutti F.
      • Corti G.
      • et al.
      Acute viral hepatitis increases liver stiffness values measured by transient elastography.
      biliary obstruction,
      • Millonig G.
      • Reimann F.M.
      • Friedrich S.
      • et al.
      Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.
      and hepatic congestion in the presence of fluid overload, such as congestive cardiac failure or end-stage renal failure.
      • Perazzo H.
      • Veloso V.G.
      • Grinsztejn B.
      • et al.
      Factors that could impact on liver fibrosis staging by transient elastography.
      The application of non-invasive methods for fibrosis assessment has certain limitations in patients on MHD.
      • Goel A.
      • Bhadauria D.S.
      • Aggarwal R.
      Hepatitis C virus infection and chronic renal disease: a review.
      People on MHD are in a state of fluid overload which may result in falsely elevated TE value and overestimation of liver fibrosis. Such a false elevation in TE may lead to either unnecessary liver biopsy to assess liver fibrosis or deferment of transplant surgery. The data on the performance of TE for liver fibrosis assessment in the MHD population is controversial. Multiple studies have attempted to study the effect of fluid overload on LS by comparing the TE before and after a single session of hemodialysis. A single session of hemodialysis may not immediately restore the euvolemic state and may fail to normalize the falsely elevated LS. True euvolemia could only be assured after the achievement of normal renal function following successful renal transplantation.
      We aimed to study the change in LS, as measured by TE, in MHD patients after successful renal transplantation and achievement of normal renal function.

      Method

      This prospective, observational study was conducted in the departments of Nephrology and Gastroenterology in Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. The participants were recruited and followed from July 2018 to June 2021. Adults on MHD for ≥2 years with prospects for renal transplantation were included. Patients were excluded if they had either (i) co-existing cardiac diseases on clinical examination, electrocardiography, or echocardiographic evaluation; (ii) clinical, laboratory, or radiological evidence of liver or biliary disease (total serum bilirubin >2 mg/dL or serum alanine aminotransferase [ALT] > 80 IU/L, i.e., >2 times upper limits of normal); (iii) active or resolved hepatitis B or HCV infection, alcoholic liver disease, or pre-existing CLD; (iv) anti-HIV positivity; (v) focal lesion in the liver such as simple cyst; (vi) clinical or laboratory evidence of active bacterial or viral infections; (vii) patients on peritoneal dialysis; (viii) patients with ascites, regardless of its cause; (ix) history of significant alcohol intake (men >30 g/wk; women >20 g/wk); or (x) body mass index beyond the normal range of 18.5–25.0 kg/m2.
      Each participant underwent LS measurement on two occasions. The first TE measurement was done within two weeks prior to renal transplantation (pre-transplant observation, pre-Tx LS); the second measurement was done after ≥3 months of renal transplantation in those with normal functioning allograft (post-transplant observation, post-Tx LS). LS was measured with TE (FibroScan®, Echosens, France). All the LS measurements were done in the morning hours after overnight fasting by a single operator (TSN) who had the experience of >5000 examinations. All TE measurements were done within 24 h of their last hemodialysis session. To abide by the widely accepted international recommendations, an LS measurement was considered to be acceptable if it satisfied the following characteristics (i) a minimum of ten readings were taken with (ii) a success rate of ≥60% and (iii) ratio of interquartile range/median being ≤0.30. The median of the ten successful readings was taken as the patient's TE score.
      • Castera L.
      • Foucher J.
      • Bernard P.H.
      • et al.
      Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.
      The summary analysis of global data on LS in healthy individual suggests mean TE up to 4.7 KPa is normal in people with BMI <30 kg/m2.
      • Bazerbachi F.
      • Haffar S.
      • Wang Z.
      • et al.
      Range of normal liver stiffness and factors associated with increased stiffness measurements in apparently healthy individuals.
      The hepatology colleagues consider LS > 7.0 as evidence suggestive of significant liver fibrosis.
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      Accepting a more conservative approach to making our results more reliable, we classified the participants with pre-Tx LS ≤ 7.0 KPa and >7.0 KPa as “Group I” and “Group II,” respectively.
      We also calculated two other indices for the assessment of liver fibrosis (aspartate aminotransferase [AST] platelet ratio, AST-platelet ratio index [APRI], and fibrosis-4 index [FIB-4]).
      EASL-ALEH Clinical Practice Guidelines
      Non-invasive tests for evaluation of liver disease severity and prognosis.
      Their calculation needs laboratory values for ALT, AST, and platelet counts. All the necessary laboratory investigations were done in the fasting state on the day of LS measurement. The APRI and FIB-4 >1.5 and 3.25 are universally accepted as an indicator of significant fibrosis.
      • Sterling R.K.
      • Lissen E.
      • Clumeck N.
      • et al.
      Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.

      Statistical analysis

      The LS, in patients on MHD without any evidence of liver disease, is reported as 7.7 ± 2.3 KPa.
      • Zjačić Puljiz D.
      • Delić Jukić I.K.
      • Puljiz M.
      • et al.
      Which factors influence liver stiffness measured by real-time two dimensional shear wave elastography in patients on maintenance hemodialysis?.
      We estimated the required sample size, assuming the mean difference of 1.0 ± 2.3 KPa in paired observation taken before and after renal transplantation, as 43 pairs to achieve a power of 80% and a level of significance of 5% using two-sided tests of significance. Assuming a 10% data loss due to various reasons, we plan to include 47 patients. Categorical and numerical data are expressed as ratios/proportions and mean (standard deviation, SD). The categorical variable was compared using the chi-square test. The unpaired and paired numerical data are compared using a t-test. Data were analyzed with STATA/IC 16.1 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC).
      The study was approved by the institute ethics committee (2017-171-IMP-99B), and the participants were enrolled after obtaining written consent. The study was performed in accordance with the 1964 Declaration of Helsinki and its later amendments.

      Results

      Of the 78 patients enrolled, 45 could undergo renal transplantation—two patients who had organ rejection after transplantation were excluded. Data from the remaining 43 patients, who achieved normal renal function after transplantation, were included in the analysis. Most of the participants were young males (males 42 [97.7%]; age 32 [11] years).
      Pre-transplant clinical characteristics, laboratory parameters, and liver fibrosis parameters of the participants are summarized in Table 1. Among 43 patients, 22 participants (51.2%) with normal LS were included in Group I, whereas 21 participants (48.8%) with elevated LS were included in Group II. The characteristics of the participants in Group I and Group II were comparable (Table 1). The participants were reassessed after 307 (198) days after renal transplantation. The changes in laboratory parameters, an indicator of liver fibrosis, and LS scores are summarized in Table 2.
      Table 1Pre-transplant Clinical Characteristics, Laboratory Investigations, and Indices of Liver Fibrosis in Study Participants.
      ParametersAll the participants (n = 43)Subgroups
      Group I: Participants with LS ≤ 7.0 Kilopascal (n = 22)Group II: Participants with LS > 7.0 Kilopascal (n = 21)P value
      Males42 (97)21 (95)21 (100)1.00
      Age (years)32 (11)29 (9)36 (11)0.02
      Hemoglobin (g/dL)10 (2.5)10.5 (2.1)9.8 (2.8)0.23
      Platelet (×109/L)176 (49)169 (56)184 (41)0.34
      Creatinine (mg/dL)8.0 (3.1)8.0 (3.1)7.2 (2.9)0.12
      Total bilirubin (mg/dL)0.6 (0.3)0.6 (0.3)0.7 (0.3)0.47
      ALT (IU/L)21 (14)22 (12)21 (16)0.81
      AST (IU/L)23 (11)23 (10)23 (13)0.88
      Albumin (g/dL)4.4 (0.7)4.5 (0.6)4.2 (0.7)0.13
      Liver stiffness (KPa)8.5 (7.3)5.5 (1.0)11.8 (9.5)<0.01
      Controlled attenuation parameter (dB/m)201 (40)200 (27)203 (51)0.77
      APRI0.35 (0.20)0.38 (0.21)0.32 (0.20)0.39
      FIB-40.97 (0.49)0.91 (0.46)1.03 (0.52)0.42
      Interval between transplant and repeat measurement (days)307 (198)303 (217)312 (182)0.89
      Etiology of kidney disease0.45
       CGN22 (51)10 (45)12 (57)
       DN13 (30)7 (32)5 (24)
       CIN8 (19)5 (23)4 (19)
      Note: Data are presented as number (%) or mean (SD). ALT, alanine aminotransferase; AST, aspartate aminotransferase; APRI, AST-platelet ratio index; FIB-4, fibrosis-4 index; CGN, chronic glomerulonephritis; DN, diabetic nephropathy; IGN, interstitial glomerulonephritis. groups are compared using chi-square and t-test.
      Table 2Comparison of Laboratory Parameters, Liver Fibrosis Indices, and Liver Stiffness Before and After Kidney Transplantation.
      ParametersOverall (n = 43)Group I: Participants with LS ≤ 7.0 Kilopascal (n = 22)Group II: Participants with LS > 7.0 Kilopascal (n = 21)
      Before TxAfter TxP-valueBefore TxAfter TxP -valueBefore TxAfter TxP -value
      Platelet (×109/L)176 (49)159 (48)0.02169 (56)150 (45)0.12184 (41)169 (52)0.10
      ALT (IU/L)21 (14)30 (18)0.0222 (12)33 (20)0.0421 (16)26 (14)0.28
      AST (IU/L)23 (11)26 (15)0.2723 (10)27 (16)0.3023 (13)25 (15)0.60
      Creatinine (mg/dL)8.0 (3.1)1.4 (0.5)<0.018.0 (3.1)1.4 (0.5)<0.017.2 (2.9)1.4 (0.6)<0.01
      Liver stiffness (KPa)8.5 (7.3)6.7 (3.1)0.025.5 (1.0)5.7 (1.2)0.4211.8 (9.5)7.7 (4.0)0.01
      Controlled attenuation parameter (dB/m)201 (40)220 (45)0.01200 (27)205 (25)0.50203 (51)236 (56)<0.01
      APRI0.35 (0.20)0.52 (0.71)0.110.38 (0.21)0.65 (0.96)0.200.32 (0.20)0.39 (0.23)0.22
      FIB-40.97 (0.49)1.08 (0.67)0.160.91 (0.46)0.96 (0.44)0.581.03 (0.52)1.20 (0.84)0.18
      Note: Data are presented as number (%) or mean (SD). ALT, alanine aminotransferase; AST, aspartate aminotransferase; APRI, AST-platelet ratio index; FIB-4, fibrosis-4 index; Tx, transplantation. groups are compared using non-parametric Wilcoxon signed rank test.
      In Group II, LS was normalized in 12 of the 21 participants (57.1%) participants on repeat assessment performed after a mean (SD) 312 (182) days of transplantation. In Group I, three of the 22 (13.6%) showed elevation of LS beyond 7.0 KPa on repeat measurement after a mean (SD) 303 (217) days of transplantation (Fig. 1). The mean reduction in LS values among the overall cohort and Group II were 1.8 KPa and 4.1 KPa, respectively. The mean decrease in stiffness in Group II was significantly higher than in Group I (Table 2). The mean increase in LS in Group I was +0.2 KPa.
      Figure 1
      Figure 1Number of participants with normal liver stiffness (≤7.0 KPa) and elevated liver stiffness (>7.0 KPa) before and after successful renal transplantation.
      The median (interquartile range, IQR) LS of the cohort before and after transplantation were 6.9 (5.5–8.4) and 6.0 (4.6–7.8), respectively. The median interval between the repeated measurements was 246 (119–470) days. The median LS in Group I, measured after an interval of 268 (99–470) days, was changed from 5.6 (4.9–6.1) KPa to 5.8 (4.5–6.3) KPa. Similarly, the median LS in Group II, measured after an interval of 246 (175–460) days, was changed from 8.4 (7.7–11.1) KPa to 6.3 (4.9–8.5) KPa.
      Pre-transplant APRI and FIB-4 and post-transplant FIB-4 for none of the participants were suggestive of significant liver fibrosis. For one participant, the post-transplant APRI was increased from 0.35 to 4.8.

      Discussion

      We followed a cohort of 43 MHD patients and reported the changes in their non-invasive parameters of liver fibrosis, including LS as assessed by TE, APRI, and FIB-4. These parameters were evaluated after a mean interval of 307 (198) days after successful kidney transplantation. Pre-transplant LS were elevated among half of the participants. The mean value of TE in Group II participants was reduced from 11.8 KPa before transplant to 7.7 KPa after transplant (P < 0.01) on repeat measurement after a mean interval of 312 (182) days.
      Liver biopsy, the gold standard for liver fibrosis assessment, has several disadvantages. Some of the major disadvantages are invasive nature, need for hospitalization, inherent financial expenses, pain during the procedure, requires expertise to perform and interpret the biopsy, and finite risk of complications including death.
      • Rockey D.C.
      • Caldwell S.H.
      • Goodman Z.D.
      • et al.
      Liver biopsy.
      The risk of bleeding following liver biopsy is further increased by secondary to uremia in MHD patients.
      • Rockey D.C.
      • Caldwell S.H.
      • Goodman Z.D.
      • et al.
      Liver biopsy.
      The use of non-invasive methods and indices has almost replaced liver biopsy for the assessment of liver fibrosis. Three non-invasive methods, namely APRI, FIB-4, and LS measurement by TE, are the most widely and extensively validated and have the best diagnostic performances.
      EASL-ALEH Clinical Practice Guidelines
      Non-invasive tests for evaluation of liver disease severity and prognosis.
      The calculation of APRI and FIB-4 indices require serum ALT and AST levels. The serum levels of ALT and AST are relatively lower among MHD patients
      • Sette L.H.
      • Almeida Lopes E.P.
      Liver enzymes serum levels in patients with chronic kidney disease on hemodialysis: a comprehensive review.
      than those with normal renal function, which underestimates the fibrosis scores and limits their application to the dialysis population. In a cohort of 165 dialysis patients with chronic HCV infection, the cut-off to define cirrhosis by APRI was 0.28 and 1.91, respectively,
      • Lee J.J.
      • Wei Y.J.
      • Lin M.Y.
      • et al.
      The applicability of non-invasive methods for assessing liver fibrosis in hemodialysis patients with chronic hepatitis C.
      which are much lower than 2.0 and 3.25 recommended for those with normal renal function.
      European Association for the Study of the Liver
      Electronic address eee, European association for the study of the L. EASL recommendations on treatment of hepatitis C 2018.
      TE measures LS and has gained momentum for fibrosis assessment in patients with normal function. For the population with normal renal function, significant fibrosis, severe fibrosis, and cirrhosis are given by TE value ≥ 7.0 KPa, ≥9.5 KPa, ≥12.5 KPa, respectively.
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      LS is falsely elevated in the presence of hepatic congestion secondary to biliary obstruction, back pressure due to congestive cardiac failure, edema secondary to acute hepatitis insult, or volume overload. Advanced renal failure is a state of chronic volume overload and can falsely increase the LS. However, the diagnostic performance of TE is found to be comparable to liver biopsy in MHD patients with liver disease.
      • Liu C.H.
      • Liang C.C.
      • Huang K.W.
      • et al.
      Transient elastography to assess hepatic fibrosis in hemodialysis chronic hepatitis C patients.
      The data on LS in MHD patients without liver disease are minimal. In a recent study of 171 MHD patients without risk factors for liver disease, 21% of participants had LS suggestive of advanced fibrosis.
      • Syed T.
      • Chadha N.
      • Kumar D.
      • et al.
      Non-invasive assessment of liver fibrosis and steatosis in end-stage renal disease patients undergoing renal transplant evaluation.
      However, the fibrosis was not assessed with liver biopsy in this study. Another study, although it included only 17 participants, found LS suggestive of significant fibrosis in 41%.
      • Kellner P.
      • Anadol E.
      • Huneburg R.
      • et al.
      The effect of hemodialysis on liver stiffness measurement: a single-center series.
      The data from previous studies performed in MHD patients with chronic viral hepatitis are inconsistent about the effect of a single session of hemodialysis on LS. Studies have shown that following a single session of hemodialysis, the LS may reduce,
      • Taneja S.
      • Borkakoty A.
      • Rathi S.
      • et al.
      Assessment of liver fibrosis by transient elastography should Be done after hemodialysis in end stage renal disease patients with liver disease.
      remain unchanged,
      • Khunpakdee N.
      • Jayanama K.
      • Kaewdoung P.
      • et al.
      Transient elastography in end-stage renal disease patients on hemodialysis: the effect of net fluid withdrawal.
      or increase.
      • Kellner P.
      • Anadol E.
      • Huneburg R.
      • et al.
      The effect of hemodialysis on liver stiffness measurement: a single-center series.
      All these studies had attempted to study the effect of volume overload on LS by removing the fluid following a single session of hemodialysis. A hemodialysis session may not be adequate to restore the euvolemia; further, it may take time to reduce the LS after the restoration of euvolemia.
      Our study is the first to report the change in LS after successful renal transplantation and normalization of renal function. Our data suggested that the LS of the participants who had normal stiffness before transplantation does not change after transplantation. In contrast, the LS of those with high values before transplantation is reduced to normal after transplantation in a proportion of patients. The other liver fibrosis indices, such as APRI and FIB-4, do not change after transplantation, which further supports the hypothesis that liver fibrosis was unlikely to be responsible for the elevation of LS among people on MHD. Our data suggest that in almost half of MHD patients with elevated LS, the stiffness seems to be falsely elevated, and liver biopsy may be avoided in them.
      Our study has a limitation of the long interval between the two LS measurements. We had planned for a repeat LS measurement after three months of renal transplantation, but it was delayed due to the ongoing COVID-19 pandemic. The long interval could have led to liver steatosis, which is reflected in the increased controlled attenuation parameter (CAP). New-onset fatty liver disease is common among renal transplant recipients.
      • Mikolasevic I.
      • Racki S.
      • Lukenda V.
      • et al.
      Nonalcoholic Fatty liver disease in renal transplant recipients proven by transient elastography.
      Steatosis is likely to increase the LS, which will lead to underestimation of the reduction in LS following transplantation which makes our results more robust to believe.
      In conclusion, LS in people on MHD may be falsely elevated due to chronic fluid overload, and it does not necessarily suggest significant liver fibrosis. The LS is likely to normalize in many of them who follow renal transplantation.

      Credit authorship contribution statement

      Concept: Amit Goel, Dharmendra Singh Bhadauria, Praveer Rai, Narayan Prasad.
      Design: Amit Goel, Dharmendra Singh Bhadauria, Anupma Kaul, Praveer Rai, Narayan Prasad.
      Funding: Dharmendra Singh Bhadauria, Anupma Kaul, Tajwar Singh Negi.
      Data collection: Amit Goel, Dharmendra Singh Bhadauria, Prachi Tiwari, Pankaj Kumar, Anupma Kaul, Tajwar Singh Negi, Praveer Rai.
      Narayan Prasad: Prachi Tiwari, Pankaj Kumar, Pankaj Kumar, Anupma Kaul, Tajwar Singh Negi, Narayan Prasad.
      Data interpretation: Amit Goel, Dharmendra Singh Bhadauria, Praveer Rai, Narayan Prasad.
      First draft: Prachi Tiwari, Pankaj Kumar, Anupma Kaul.
      Final draft approval: Amit Goel, Dharmendra Singh Bhadauria, Prachi Tiwari, Pankaj Kumar, Anupma Kaul, Tajwar Singh Negi, Praveer Rai, Narayan Prasad.

      Conflicts of interest

      The authors have none to declare.

      Acknowledgements

      None.

      Funding

      Dr. Dharmendra Singh Bhadauria has received an intramural research grant from Sanjay Gandhi Postgraduate Institute of Medical Sciences ( 2017-171-IMP-99B ). Prachi Tiwari received financial support from the Indian Council of Medical Research by extramural research grant no VIR/18/2018/ECD-I .

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