successfully conducted the first simultaneous liver - kidney transplant ( slkt ) in 1983 on a patient with chronic kidney allograft rejection and liver cirrhosis , this procedure has become the most effective method for the treatment of combined end - stage liver disease and renal failure . the number of patients with end - stage liver disease and renal insufficiency receiving slkt has increased remarkably , particularly since the introduction of the model for end - stage liver disease ( meld ) scoring system by the united network for organ sharing ( unos ) in 2002 . statistics showed that the number of slkt recipients in the united states has quadrupled from 1998 to 2006 . in addition , the survival rate of slkt recipients has significantly increased following the adoption of meld . the primary causes of end - stage liver disease are cirrhosis caused by viral hepatitis , alcoholic cirrhosis , liver cancer , and congenital liver diseases . while hepatitis c is the leading cause in western countries , hepatitis b is the most prevalent type in china . epidemiological studies have shown that more than 800 million people have been infected with hepatitis b in china . up to 10.31% of the chinese population is hepatitis b surface antigen ( hbsag)-positive . in china , up to 80% of patients with liver failure requiring liver transplant are due to hepatitis b - associated causes . relapse of hepatitis b after liver transplant can reduce the patient s probability of survival by inducing graft dysfunction , recurrence of liver cancer , and lymphatic proliferation . a previous study reported that slkt for hepatitis c , non - alcoholic steatosis and hepatocellular cancer could be associated with worst outcomes compared with other slkt indications . however , few studies have reported the effectiveness of slkt and hepatitis b recurrence in hepatitis b carriers receiving slkt . previous studies have compared the outcome of slkt mainly to outcomes of liver transplant ( lt ) patients with normal renal function as controls [ 1216 ] , while comparison to lt patients with renal insufficiency has been largely ignored . a comparison between slkt recipients with hepatitis b infection and lt recipients with renal insufficiency and hepatitis b infection could provide a more objective assessment of the outcome of slkt associated with hepatitis b. in addition , which indicators can predict the long - term outcomes of liver transplant patients still need to be assessed . therefore , this comparative study analyzed rates of postoperative infection , rejection , long - term survival , and relapse of hepatitis b in hepatitis b carriers receiving slkt at the organ transplant center of the shanghai first people s hospital . this was a retrospective analyses in 21 patients ( male : 19 , female : 2 ) who underwent slkt at the organ transplant center of shanghai first people s hospital , shanghai jiaotong university , between january 2001 and may 2005 . recipients of slkt were selected based on the following criteria : 1 ) irreversibly compromised renal function confirmed by preoperative examination , including serum creatinine levels > 133 mol / l lasting for 1 month continuously ; 2 ) high - risk factors for kidney diseases , such as diabetes and hypertension ; and 3 ) massive proteinuria and/or requiring renal replacement therapy for more than 3 weeks . liver and kidney allografts for the same patient came from the same donor , whom was not necessarily a relative . panel reactive antibody ( pra ) class i of recipients was 028% , and class ii was 017% . the study period also included 25 patients who underwent lt alone with renal insufficiency ( preoperative serum creatinine levels > 133 mol / l ) . twenty - five recipients developed renal insufficiency due to hepatorenal syndrome without acute tubular necrosis and renal parenchymal disease . this study was approved by the ethical committee of the shanghai first people s hospital , and written informed consent was obtained from each patient . written consent has been obtained from all donors at the time of their donation . criteria for slkt : 1 ) end - stage liver disease and irreversible kidney failure ; 2 ) congenital diseases involving the liver and kidney ; 3 ) liver failure and chronic kidney disease ( ckd ) with gfr 30 ml / min ; 4 ) acute kidney injury ( aki ) with creatinine levels 176.8 mol / l and dialysis 8 weeks ; or 5 ) liver failure and ckd and biopsy demonstrating > 30% glomerulosclerosis or fibrosis . if there was no evidence to prove irreversible renal damage , liver transplantation alone was preferred . whether patients with hepatorenal syndrome should undergo slkt was controversial , and each patient was discussed . when patients with hepatorenal syndrome were on dialysis for < 4 weeks , liver transplant alone was performed . biochemical indicators ( including serum creatinine , total bilirubin , and aspartate aminotransferase ( ast ) levels ) were followed up for 5 years in all transplant recipients . lt patients were stratified according to the severity of aki as described by the risk , injury , failure , loss and endstage kidney disease ( rifle ) classification : risk , injury or failure . early- and late - stage postoperative complications , postoperative infections , rejection , and long - term survival were also recorded . the diagnosis of acute renal allograft rejection was primarily based on recipients clinical presentation , biochemical indicators ( a 25% increase of serum creatinine levels or more ) , and histopathological biopsy . the diagnosis of acute hepatic allograft rejection required increases in serum ast levels and/or in total bile acids , and was confirmed by liver biopsy . treatment of acute allograft rejection mainly relied on methylprednisolone sodium succinate pulse therapy , an increase in the dose of immunosuppressants , and/or change of types of immunosuppressive agent . the induction regimen of anti - cd25 monoclonal antibody ( daclizumab or basiliximab ) was prescribed to all patients . slkt recipients received a triple maintenance therapy of calcineurin inhibitor ( cni ; cyclosporine and tacrolimus ) , mycophenolate mofetil ( mmf ) and prednisolone ( pred ) , while lt recipients received the steroid - free regimen of cni + mmf . nucleoside analogues coupled with low - dose hepatitis b immunoglobulin ( hbig ) were given to prevent hepatitis b relapse . preoperative nucleoside analogue therapy was followed by intraoperative hbig 2000 u. postoperative combined therapy was administered with maintenance hbig twice per week . within 6 months of transplantation , survival rates of recipients and allografts were analyzed using the kaplan - meier and log - rank methods . continuous data were analyzed using the student s t - test , and categorical variables using the chi - square test . this was a retrospective analyses in 21 patients ( male : 19 , female : 2 ) who underwent slkt at the organ transplant center of shanghai first people s hospital , shanghai jiaotong university , between january 2001 and may 2005 . recipients of slkt were selected based on the following criteria : 1 ) irreversibly compromised renal function confirmed by preoperative examination , including serum creatinine levels > 133 mol / l lasting for 1 month continuously ; 2 ) high - risk factors for kidney diseases , such as diabetes and hypertension ; and 3 ) massive proteinuria and/or requiring renal replacement therapy for more than 3 weeks . liver and kidney allografts for the same patient came from the same donor , whom was not necessarily a relative . panel reactive antibody ( pra ) class i of recipients was 028% , and class ii was 017% . the study period also included 25 patients who underwent lt alone with renal insufficiency ( preoperative serum creatinine levels > 133 mol / l ) . twenty - five recipients developed renal insufficiency due to hepatorenal syndrome without acute tubular necrosis and renal parenchymal disease . this study was approved by the ethical committee of the shanghai first people s hospital , and written informed consent was obtained from each patient . written consent has been obtained from all donors at the time of their donation . criteria for slkt : 1 ) end - stage liver disease and irreversible kidney failure ; 2 ) congenital diseases involving the liver and kidney ; 3 ) liver failure and chronic kidney disease ( ckd ) with gfr 30 ml / min ; 4 ) acute kidney injury ( aki ) with creatinine levels 176.8 mol / l and dialysis 8 weeks ; or 5 ) liver failure and ckd and biopsy demonstrating > 30% glomerulosclerosis or fibrosis . if there was no evidence to prove irreversible renal damage , liver transplantation alone was preferred . whether patients with hepatorenal syndrome should undergo slkt was controversial , and each patient was discussed . when patients with hepatorenal syndrome were on dialysis for < 4 weeks , liver transplant alone was performed . biochemical indicators ( including serum creatinine , total bilirubin , and aspartate aminotransferase ( ast ) levels ) were followed up for 5 years in all transplant recipients . lt patients were stratified according to the severity of aki as described by the risk , injury , failure , loss and endstage kidney disease ( rifle ) classification : risk , injury or failure . early- and late - stage postoperative complications , postoperative infections , rejection , and long - term survival were also recorded . the diagnosis of acute renal allograft rejection was primarily based on recipients clinical presentation , biochemical indicators ( a 25% increase of serum creatinine levels or more ) , and histopathological biopsy . the diagnosis of acute hepatic allograft rejection required increases in serum ast levels and/or in total bile acids , and was confirmed by liver biopsy . treatment of acute allograft rejection mainly relied on methylprednisolone sodium succinate pulse therapy , an increase in the dose of immunosuppressants , and/or change of types of immunosuppressive agent . the induction regimen of anti - cd25 monoclonal antibody ( daclizumab or basiliximab ) was prescribed to all patients . slkt recipients received a triple maintenance therapy of calcineurin inhibitor ( cni ; cyclosporine and tacrolimus ) , mycophenolate mofetil ( mmf ) and prednisolone ( pred ) , while lt recipients received the steroid - free regimen of cni + mmf . nucleoside analogues coupled with low - dose hepatitis b immunoglobulin ( hbig ) were given to prevent hepatitis b relapse . preoperative nucleoside analogue therapy was followed by intraoperative hbig 2000 u. postoperative combined therapy was administered with maintenance hbig twice per week . within 6 months of transplantation , survival rates of recipients and allografts were analyzed using the kaplan - meier and log - rank methods . continuous data were analyzed using the student s t - test , and categorical variables using the chi - square test . meld scores , child - pugh scores , and incidence of preoperative dialysis were not significantly different between slkt and lt recipients . however , slkt recipients had lower egfr ( p=0.003 ) and higher preoperative serum creatinine levels ( p=0.004 ) , lower serum ast levels , and lower total serum bilirubin levels than lt recipients ( table 2 ) . four slkt recipients died : 2 died due to hepatitis b relapse and graft - versus - host disease within 2 months of surgery ; 1 discontinued lamivudine against medical advice and died due to hepatitis b relapse and subsequent acute liver failure 14 months after surgery ; and 1 died due to systemic infection 24 months after surgery . recipients had a 1-year survival rate of 90.5% , a 3-year survival rate of 81.0% , and a 5-year survival rate of 81.0% ( table 2 ) . eleven recipients died ( table 3 ) : 6 died due to fulminant hepatic failure and subsequent renal failure within 1 month of surgery , which is defined as a clinical syndrome developing as a result of massive necrosis of liver cells or following any other cause of sudden and severe impairment of hepatic function occurring in patients without pre - existing or at least well - compensated liver disease ; 1 died due to primary graft dysfunction ; 1 died due to portal vein thrombosis ; and 1 died due to bleeding of an inferior vena cava aneurysm . another 2 patients died due to tumor recurrence during long - term follow - up . recipients had a 1-year survival rate of 60.0% , a 3-year survival rate of 56.0% , and a 5-year survival rate of 56.0% ( table 2 ) . kaplan - meier survival analysis showed that slkt recipients had a higher survival rate than that of lt recipients ( p=0.025 ) , particularly at 1 year post - transplant ( figure 1 ) . seven cases of hepatic allograft rejection occurred among the slkt recipients ; 4 developed rejection within 1 month of surgery , and the others developed rejection at 12 months , 18 months , and 37 months after surgery , respectively . four lt recipients developed allograft rejection ( table 2 ) : 2 cases of allograft rejection occurred within 1 month of surgery , while the other 2 cases occurred at 6 months and 12 months of surgery , respectively . univariate analyses revealed that slkt recipients had a higher but insignificant incidence of infection at an early postoperative stage , compared with lt recipients . slkt recipients had significantly longer stay in the intensive care unit ( icu ) and longer total length of hospital stay , compared with lt recipients . on the other hand , lt recipients demonstrated higher incidence of renal failure and higher mortality at an early postoperative stage compared to slkt recipients ( p=0.005 ) ( table 2 ) . slkt recipients and lt recipients demonstrated sero - clearance of hbsag within 3 months after surgery . however , slkt recipients experienced a significantly higher rate of hepatitis b relapse ( 38.1% , p=0.007 ) compared with lt recipients . steroid therapy for other subjects was discontinued , and nucleoside analogues coupled with high - dose hbig ( hbig 20 000 u / d14d ) were given . following the treatment , the patients had serologic hepatitis b virus ( hbv ) dna test results that showed undetectable levels of hbv ( table 4 ) . risk factors for high mortality ( 32% ) at an early stage after lt were analyzed using univariate and multivariate analyses . according to univariate analyses ( table 5 ) , patients who died at an early stage after surgery had significantly higher preoperative serum creatinine levels ( 239.5107.7 mol / l ) than survivors ( 146.021.6 mol / l ) , and had significantly lower egfr levels ( 30.812.7 ml / min/1.73 m ) than survivors ( 47.18.7 ml / min/1.73 m ) . the early death recipients after lt had higher rifle stage than survivors ( 75% vs. 11.8 , p=0.004 ) . compared with survivors , patients who died during the study had significantly higher preoperative meld scores and child - pugh scores . in addition , a higher incidence rate of postoperative renal failure ( 24% ) was associated with mortality compared with that of survivors ( 4% , p=0.001 ) . multivariate analysis revealed that postoperative renal failure ( p=0.003 ; or 48 ; 95%ci : 3.65631.76 ) and higher rifle stage ( p=0.012 , or 8 ; 95%ci : 1.5638.22 ) were independent risk factors for mortality after liver transplant ( table 6 ) . meld scores , child - pugh scores , and incidence of preoperative dialysis were not significantly different between slkt and lt recipients . however , slkt recipients had lower egfr ( p=0.003 ) and higher preoperative serum creatinine levels ( p=0.004 ) , lower serum ast levels , and lower total serum bilirubin levels than lt recipients ( table 2 ) . four slkt recipients died : 2 died due to hepatitis b relapse and graft - versus - host disease within 2 months of surgery ; 1 discontinued lamivudine against medical advice and died due to hepatitis b relapse and subsequent acute liver failure 14 months after surgery ; and 1 died due to systemic infection 24 months after surgery . recipients had a 1-year survival rate of 90.5% , a 3-year survival rate of 81.0% , and a 5-year survival rate of 81.0% ( table 2 ) . eleven recipients died ( table 3 ) : 6 died due to fulminant hepatic failure and subsequent renal failure within 1 month of surgery , which is defined as a clinical syndrome developing as a result of massive necrosis of liver cells or following any other cause of sudden and severe impairment of hepatic function occurring in patients without pre - existing or at least well - compensated liver disease ; 1 died due to primary graft dysfunction ; 1 died due to portal vein thrombosis ; and 1 died due to bleeding of an inferior vena cava aneurysm . another 2 patients died due to tumor recurrence during long - term follow - up . recipients had a 1-year survival rate of 60.0% , a 3-year survival rate of 56.0% , and a 5-year survival rate of 56.0% ( table 2 ) . kaplan - meier survival analysis showed that slkt recipients had a higher survival rate than that of lt recipients ( p=0.025 ) , particularly at 1 year post - transplant ( figure 1 ) . seven cases of hepatic allograft rejection occurred among the slkt recipients ; 4 developed rejection within 1 month of surgery , and the others developed rejection at 12 months , 18 months , and 37 months after surgery , respectively . four lt recipients developed allograft rejection ( table 2 ) : 2 cases of allograft rejection occurred within 1 month of surgery , while the other 2 cases occurred at 6 months and 12 months of surgery , respectively . univariate analyses revealed that slkt recipients had a higher but insignificant incidence of infection at an early postoperative stage , compared with lt recipients . slkt recipients had significantly longer stay in the intensive care unit ( icu ) and longer total length of hospital stay , compared with lt recipients . on the other hand , lt recipients demonstrated higher incidence of renal failure and higher mortality at an early postoperative stage compared to slkt recipients ( p=0.005 ) ( table 2 ) . slkt recipients and lt recipients demonstrated sero - clearance of hbsag within 3 months after surgery . however , slkt recipients experienced a significantly higher rate of hepatitis b relapse ( 38.1% , p=0.007 ) compared with lt recipients . steroid therapy for other subjects was discontinued , and nucleoside analogues coupled with high - dose hbig ( hbig 20 000 u / d14d ) were given . following the treatment , the patients had serologic hepatitis b virus ( hbv ) dna test results that showed undetectable levels of hbv ( table 4 ) . risk factors for high mortality ( 32% ) at an early stage after lt were analyzed using univariate and multivariate analyses . according to univariate analyses ( table 5 ) , patients who died at an early stage after surgery had significantly higher preoperative serum creatinine levels ( 239.5107.7 mol / l ) than survivors ( 146.021.6 mol / l ) , and had significantly lower egfr levels ( 30.812.7 ml / min/1.73 m ) than survivors ( 47.18.7 ml / min/1.73 m ) . the early death recipients after lt had higher rifle stage than survivors ( 75% vs. 11.8 , p=0.004 ) . compared with survivors , patients who died during the study had significantly higher preoperative meld scores and child - pugh scores . in addition , a higher incidence rate of postoperative renal failure ( 24% ) was associated with mortality compared with that of survivors ( 4% , p=0.001 ) . multivariate analysis revealed that postoperative renal failure ( p=0.003 ; or 48 ; 95%ci : 3.65631.76 ) and higher rifle stage ( p=0.012 , or 8 ; 95%ci : 1.5638.22 ) were independent risk factors for mortality after liver transplant ( table 6 ) . the effectiveness of slkt in patients with hepatitis viral infection had not been thoroughly examined previously . in western countries , hepatitis c virus is the primary cause of end - stage liver disease and subsequently renal impairment . hepatitis c carriers who received slkt have demonstrated a 5-year survival rate of 68% . however , in asian countries , including china , most liver transplant recipients are hepatitis b virus carriers , in whom the outcome of slkt is less understood . this study reported the largest number of hepatitis b patients receiving slkt , in which the 1- , 3- , and 5-year survival rates were 90.5% , 81.0% , and 81.0% , respectively . singal et al . have reported that slkt for hepatitis c , non - alcoholic steatosis and hepatocellular cancer could be associated with worst outcomes compared with other slkt indications ; however , they did not include patients with hepatitis b , which is the most common indication for liver transplantation due to liver failure in china . slkt recipients had significantly higher 1-year survival rate ( 90.5% ) , compared with lt recipients with hepatitis b infection and renal failure . this finding suggested that slkt was effective in improving the survival rate of transplant recipients with renal insufficiency . compared with lt alone , slkt was associated with significantly longer icu stay , longer total hospital stay , and higher incidence of postoperative early - stage infection ( 38.1% vs. 20% ) , which might be related to the greater surgical trauma and higher incidence of complications . in addition , the healthcare system in china requires that the patients are completely symptom - free at discharge , which could explain , at least in part , this longer hospital stay . the incidence of acute allograft rejection between slkt recipients ( 33.3% ) and lt recipients ( 16% ) did not reach statistical significance , suggesting that slkt failed to decrease the incidence of acute hepatic allograft rejection . these results are comparable with previous studies , but this comparison should be made with caution since these previous studies evaluated patients without hepatitis b virus infection [ 12,1416 ] . high mortality was observed in the lt group , which could be attributable to the fact that these patients were with kidney dysfunction , as shown by the multivariate analysis . in addition , even if the meld score was similar between the 2 groups , creatinine and bilirubin levels were higher in the lt group , which could be another part of the reason for the high mortality observed in this group . in addition , some other articles have reported a mortality rate from fulminant hepatic failure as high as 90% after transplantation . a number of factors may also be associated with death after liver transplantation , including infections and rejection . a previous study showed that primary liver graft dysfunction could predict kidney failure , but the present study was not designed to address this relationship . our study revealed that slkt was associated with a higher rate of hepatitis b recurrence than lt ( 38.1% vs. 4% ) . this finding might be due to the stronger and longer immunosuppressive therapy , particularly long - term steroids , administered to slkt recipients compared with steroid - free treatment for lt recipients . the use of steroids has been reported as a risk factor for hepatitis b relapse   and for poor survival and hepatitis c relapse . glucocorticoids can directly stimulate an enhancer region and a glucocorticoid response element in hepatitis b virus dna , thereby inducing viral transcription . glucocorticoid administration also suppresses the immune response by reducing the hbv - specific cytotoxic t cell response , and therefore hbv - dna titer increases during glucocorticoid treatment . alternatively , slkt recipients higher hepatitis b relapse rate might be related to the effect of double transplantation on recipients immune function . several previous studies have indicated that hbv can influence the survival of hepatic and renal allografts and lead to fulminant hepatic failure and renal allograft dysfunction . however , 2 subjects in our study died due to hepatic failure ; they discontinued anti - hbv medicine against medical advice and died due to fulminant hepatic failure . for the 6 slkt recipients with hepatitis b relapse , hormone therapy was discontinued and replaced by nucleoside analogues and high - dose hbig ( 20 000 u / d14d ) immediately after the relapse . therefore , slkt recipients with hbv infection should be advised of the risks for hepatitis b relapse . reasonable treatment can achieve hbv - dna sero - clearance in patients with hepatitis b relapse without affecting long - term survival . criteria for slkt for potential lt recipients with renal insufficiency are still unclear . according to the study by hanish et al .   on transplant recipients with dialysis history , slkt generates better outcome than single kidney transplantation , liver transplantation followed by dialysis , or staged liver and kidney transplantation . reached similar conclusions . in the present study , lt recipients with renal insufficiency had higher mortality at an early stage after surgery than slkt recipients ( lt vs. slkt : 32% vs. 0% ) . risk factors for death in lt recipients included lower egfr and higher rifle stage , preoperative serum creatinine levels , meld score , child - pugh score , and postoperative renal failure . although gfr is considered the best estimate of renal function than serum creatinine levels , gfr was not an independent risk factor for postoperative deaths . therefore , a gfr less than 30 ml / min is not enough to qualify for slkt . postoperative renal failure ( or=48 ) and rifle stage ( or=8 ) among lt recipients were an independent risk factor for postoperative deaths . it is reported that rifle criteria has been shown to predict clinical outcomes with a progressive increase in mortality with worsening rifle class . therefore , patients who might inevitably develop postoperative renal failure or be in need of dialysis should opt for slkt when possible . it is essential that patients with liver failure with worsening rifle class should be considered for slkt . indeed , this was a retrospective study that suffers from all the limitations inherent to this type of study . furthermore , these patients were from a single center , and the sample size was relatively small . the small number of death events in the slkt group ( 4/21 ) prevented a multivariate analysis in this group . despite longer hospital stay and higher infection rate at an early stage after surgery , slkt demonstrated satisfactory long - term survival rates in patients with hepatitis b infection . despite a higher rate of hepatitis b relapse following slkt , timely and reasonable treatments were able to prevent hepatitis b relapse from affecting long - term prognosis . therefore , slkt can achieve good long - term outcomes in patients with hepatitis b , end - stage liver disease , and renal insufficiency . for lt recipients with renal failure , postoperative renal failure and rifle stage were independent risk factors for postoperative deaths .
backgroundthe number and survival rate of simultaneous liver - kidney transplant ( slkt ) recipients have increased dramatically since 2002 . however , the long - term effectiveness of slkt in patients with hepatitis b is unknown.material/methodsforty-six patients who visited the organ transplant center of the shanghai first people s hospital between january 2001 and may 2005 had hepatitis b virus infection and renal failure ( any degree ) , and underwent organ transplantation : 21 patients underwent slkt and 25 patients underwent liver transplant ( lt ) alone.resultsthe 1- , 3- , and 5-year survival rates of slkt recipients were 90.5% , 81.0% , and 81.0% , respectively . 
 incidence of acute hepatic allograft rejection between slkt recipients and lt recipients ( 33% vs. 16% ) did not reach significance ( p=0.170 ) . despite higher infection rate , more prevalent hepatitis b relapse , and longer 
 stay in the intensive care unit , slkt recipients experienced significantly higher 1-year survival rate ( 90.5% ) compared with lt recipients ( 60% , p=0.019 ) . 
 multivariate regression analysis revealed that postoperative renal failure ( odds ratio ( or)=48 , p=0.003 ) and risk / injury / failure / loss / end - stage ( rifle ) stage ( or=8 , p=0.012 ) were independent risk factors for postoperative death after lt.conclusionsslkt in patients with hepatitis b had higher early - stage infection rate , but had a higher long - term survival rate compared with the lt group . 
 although the incidence of postoperative hepatitis b relapse in slkt recipients was higher , timely and reasonable treatment can ensure long - term survival of patients . worsening 
 rifle stage of recipients can predict high mortality when only given lt . 
 slkt might be a better choice for rifle stage 2 or 3 patients than lt alone .