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Risk factors for consequent kidney impairment and differential impact of liver transplantation on renal function

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Nephrol Dial Transplant (2010) 25: doi: /ndt/gfq093 Advance Access publication 5 March 2010 Risk factors for consequent kidney impairment and differential impact of liver transplantation
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Nephrol Dial Transplant (2010) 25: doi: /ndt/gfq093 Advance Access publication 5 March 2010 Risk factors for consequent kidney impairment and differential impact of liver transplantation on renal function Jung Pyo Lee 1, Nam Ju Heo 2, Kwon Wook Joo 2, Nam Joon Yi 3, Kyung-Suk Suh 3, Kyung Chul Moon 4, Seong Gyun Kim 5 and Yon Su Kim 1,2 1 Seoul National University Kidney Research Institute, Seoul, Korea, 2 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, 3 Department of Surgery, Seoul National University College of Medicine, Seoul, Korea, 4 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea and 5 Department of Internal Medicine, Hallym University College of Medicine, Chunchon, Korea Correspondence and offprint requests to: Yon Su Kim; Jung Pyo Lee collected data, analysed results, performed the study, wrote the manuscript and revised it. Nam Ju Heo, Kwon Wook Joo, Nam Joon Yi, Kyung-Suk Suh and Seong Gyun Kim designed the study and collected data. Kyung Chul Moon reviewed the kidney histopathology. Yon Su Kim designed the study, analysed the results and wrote, edited and revised the manuscript. Abstract Background. Chronic kidney disease (CKD) develops frequently after liver transplantation (LTx), and it is important to identify and correct risk factors that negatively affect kidney function. Risk factors have not been well evaluated in Asian countries where hepatitis B virus (HBV) infection is a dominant cause. Methods. Four hundred thirty-one Korean recipients who underwent LTx between 1997 and 2008 were analysed. CKD was defined as a sustained decrease in estimated glomerular filtration rate (egfr) of 60 (ml/min/1.73 m 2 ) for at least three consecutive months using an abbreviated Modification in Renal Disease (MDRD) formula. Results. Eighty percent of the patients had HBV-related underlying diseases. The recipients whose pretransplant egfr had been low ( 30 ml/min/1.73 m 2 ) improved their renal function after LTx, but significant functional decline occurred in recipients whose pretransplant egfr was high ( 60 ml/min/1.73 m 2 ). A multivariate Cox regression analysis revealed that the overall risk of CKD development (egfr 60 ml/min/1.73 m 2 ) was associated with old age of recipients, cyclosporine, posttransplant acute renal failure (ARF), cause [calcineurin inhibitor (CNI) nephrotoxicity] and severity of posttransplant ARF, low pretransplant egfr, pretransplant hepatorenal syndrome, pretransplant proteinuria, high Child Pugh score and high Model for End-Stage Renal Disease (MELD) score. Especially in recipients whose pre-operative egfr was high ( 60 ml/min/ 1.73 m 2 ), rapid progression of kidney disease was associated with high tacrolimus level, non-hbv disease, posttransplant ARF, cause (CNI nephrotoxicity) and severity of posttransplant ARF and Child Pugh score. CNI toxicity and focal segmental sclerosis, but not immune-complex disease, were revealed as significant contributors to CKD after LTx in HBV recipients. Conclusion. Judicious use of CNIs should be applied to liver recipients to prevent kidney dysfunction. Keywords: calcineurin inhibitor toxicity; hepatitis B virus; kidney biopsy; kidney dysfunction; liver transplantation Introduction Chronic kidney disease (CKD) is a common problem in long-term survivors after liver transplantation (LTx). The prevalence of CKD ranges from approximately 20% to 70%, and the occurrence of CKD significantly increases the mortality in liver recipients [1,2]. Recently, several studies were conducted to clarify the risk factors for CKD progression, such as the use of calcineurin inhibitors (CNIs) and preoperative kidney function [1,3,4]. Asian ethnicity, in comparison to other ethnic groups, has been suggested as a good prognostic factor for the development of CKD after LTx [1], but a reason for this has never been documented. In Western countries, liver disease caused by hepatitis C virus (HCV) linked with glomerulonephritis is the leading indication for liver transplantation, accounting for 30% to 50% of cases [1,5,6]. However, an Asian institute, specifically the Korean Society, developed a distinctive strategy for the institution of liver transplantation in treating liver failure [7]. Hepatitis B virus (HBV) infection is more prevalent in Korea as well as in other Asian countries where the vertical transmission of HBV is a major route of infection. It implies the long duration of infection, which has a potential to cause serious liver diseases such as liver cirrhosis and hepatocellular carcinoma. These distinctions between Asians and Caucasians may explain not only the difference in frequency but also in the main cause of kidney dysfunction after LTx. We previously reported the features of CKD after LTx in The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please CKD after liver transplantation 2773 Korea [8], but this report had limitations due to the insufficient number of recipients examined and the short duration of follow-up. The purpose of this study was to delineate the risk factors associated with progressive kidney dysfunction after LTx in recipients with HBV infection, the main indication for liver transplantation in Korea. Additionally, we reviewed kidney biopsy cases performed after liver transplantation in recipients with HBV infection to explain the above-mentioned ethnic differences because biopsy serves as a unique way to understand the exact cause of kidney dysfunction [5,9,10]. Materials and methods Study population We studied the clinical records of 604 consecutive Korean LTx patients who underwent LTx between 1997 and 2008 at our institute. Data from 173 recipients who received multi-organ transplantation, had a short follow-up duration ( 6 months), died within 6 months after transplantation, or were 18 years old were excluded. Medical records were reviewed retrospectively. Clinical parameters that could have influenced development of chronic kidney disease were collected, i.e. age at transplantation, gender, era, history of hypertension and diabetes mellitus, underlying disease, history of hepatocellular carcinoma, body mass index (BMI), pretransplant proteinuria, Child Pugh score, Model for End-Stage Disease (MELD) score, hepatorenal syndrome, posttransplant acute renal failure (ARF), aetiologies of ARF, history of cardiovascular disease, donor type and immunosuppressant. Also, information on the agents used to treat hepatitis B virus infection such as adefovir or tenofovir, which are known to be nephrotoxic in some patients was collected. Hepatitis B viraemic status was measured with serum HBV DNA polymerase chain reaction (PCR) at and after transplantation. immunosuppression was preferable to tacrolimus-based immunosuppression. In cases receiving cyclosporine-based treatment, the trough level was maintained between 200 and 300 ng/ml for the first 3 months and was reduced to 100~200 ng/ml thereafter. In the tacrolimus-based protocol, the trough level was 8~13 ng/ml for the first 3 months and decreased to 5~100 ng/ml thereafter. When the recipient had poor renal function at the time of operation, the trough level of CNIs was maintained at a relatively low level, especially in recipients with egfr 30 ml/min/1.73 m 2. Prednisolone was started at 20 mg/day and gradually tapered. Routine liver biopsy was performed on posttransplant day 10. Purine synthesis inhibitors such as mycophenolate mofetil were used as an initial immunosuppressive treatment based on a clinical decision that considered the pretransplant kidney function, results of the protocol biopsy and risk factors of rejection [e.g. human leukocyte antigen (HLA) mismatch]. It was more frequently used from the initiation of immunosuppression when the renal function was significantly compromised. Kidney biopsy and histopathologic lesion Kidney biopsy was performed after the need for percutaneous kidney biopsy was evaluated by nephrologists in the case of significant proteinuria ( 1.0 g/day), persistent microscopic haematuria or a progressive deterioration of renal function. Biopsy tissue was examined by light-, electron-, and immunofluorescent (IF) microscopy. All specimens were reviewed by an experienced kidney pathologist at the same time. Diabetic glomerulosclerosis was determined by light microscopy as well as IF using specific linear staining for IgG and albumin along the glomerular capillary walls and tubular basement membranes. CNI toxicity was diagnosed when biopsy specimens revealed the pattern of interstitial fibrosis with a striped appearance, nodular arteriolar hyalinosis and, later, tubular atrophy with glomerulosclerosis and arteriosclerosis. The number of focally or completely sclerosed glomeruli was scored as a percentage of the total number of glomeruli seen on each biopsy. Tubulointerstitial fibrosis was graded as +1 (0 24%), +2 (25 49%), +3 (50 74%), and +4 (75 100%). Vascular damage was also graded semiquantitatively as 0 to +3. Measurement of kidney function and definition of CKD and ARF Serum creatinine was measured with a commercially available assay based on the modified Jaffé method reported by Larsen [11]. CKD was defined as a sustained decrease in estimated glomerular filtration rate (egfr) of 60 ml/min/1.73 m 2 for at least three consecutive months using an abbreviated Modification in Renal Disease (MDRD) formula [=186 (serum creatinine mg/dl) (age) (0.742 if female)]. Severe CKD was defined as an egfr 30 ml/min/1.73 m 2 for at least three consecutive months. Posttransplant ARF was defined using the RIFLE criteria [12]. The aetiological categories of ARF, i.e. prerenal ARF, ischaemic acute tubular necrosis (ATN) and CNI nephrotoxicity were defined as described previously [13]. Hepatorenal syndrome was considered when all the major criteria of the International Ascites Club were fulfilled [14]. Statistical methods The statistical analysis was performed using SPSS 12.0 K (SPSS Inc, Chicago, IL, USA). Data were expressed as means ± SD. Continuous and categorical data were compared using the independent t-test and the chi-squared test, respectively. Cumulative incidence of CKD was calculated using the Kaplan Meier method. The Cox regression model was used to calculate unadjusted and adjusted hazard ratio (HR) and 95% confidence interval (CI) for factors that affect the development of CKD. The interactions among variables for adjustments were determined using the general linear model. To compare the effects of variables on graft survival, we used the backward stepwise selection in the Cox regression model. Logistic regression analysis was used to discover risk factors for rapid progression of kidney dysfunction. P-values 0.05 were considered significant. Definitions of other clinical parameters Hypertension was defined as a systolic blood pressure over 140 mmhg, diastolic pressure over 90 mmhg or the use of anti-hypertensive medication. Presence of diabetes mellitus was diagnosed if patients had symptoms and had a random blood glucose concentration 200 mg/dl or if fasting plasma glucose was 126 mg/dl on at least two separate measurements or if patients used antidiabetic medication. MELD scores were calculated for each patient using the following equation: (0.957 log (e) (serum creatinine mg/dl) log (e) (serum bilirubin mg/dl) log (e) (PT International normalized ratio) 0.643) 10. Proteinuria was defined as 1 or more on the dipstick urinalysis. Immunosuppressive treatment protocols A standardized immunosuppression protocol involving a combination of CNIs and steroids was initiated within 24 h of surgery. Choice of calcineurin inhibitor between cyclosporine and tacrolimus was determined by a transplantation team. In recipients with preoperative renal insufficiency, hepatitis C virus infection, or presence of diabetes, cyclosporine-based Results Baseline characteristics A total of 431 adult recipients [male:female 312:119, mean age (±SD) 48 ± 9.2 years old], were included, and the follow-up duration was 46 ± 31.4 months. Eighty percent of LTx cases were due to HBV-related diseases (liver cirrhosis and hepatocellular carcinoma) (Table 1). The proportion of viraemic patients at transplantation was 82.3% in the HBV recipients. Almost all of them were treated with antiviral agents such as lamivudine and adefovir. Hepatocellular carcinoma was found in 40% of the recipients. The deceased donor transplantation rate was 23%. During the follow-up period, biopsy-proven acute re- 2774 J.P. Lee et al. Table 1. Demographic characteristics between cyclosporine-based and tacrolimus-based immunosuppression Total (n = 431) Cyclosporine (n = 72) Tacrolimus (n = 359) P-value Male recipient 72.4% 68.1% 73.3% Recipient age (years) 48.3 ± ± ± Era % 8.3% 7.5% % 83.3% 40.9% % 8.3% 51.5% Body mass index 21.8 ± ± ± Pretransplant diabetes mellitus 14.4% 29.2% 11.4% 0.001 Duration of diabetes (years) a 4.9 ± ± ± Duration of treated diabetes (years) a 4.7 ± ± ± Pretransplant hypertension 4.4% 5.6% 4.2% Duration of anti-hypertensive therapy (years) b 5.5 ± ± ± History of cardiovascular disease 0.9% 1.4% 0.8% Pretransplant proteinuria 8.4% 6.9% 8.6% Pretransplant egfr (ml/min/1.73 m 2 ) 81.1 ± ± ± Hepatorenal syndrome 12.1% 15.3% 11.4% Posttransplant ARF 27.4% 36.1% 25.6% Cause of ARF c Ischaemic ATN 44.1% 42.3% 44.6% Prerenal ARF 27.1% 26.9% 27.2% CNI toxicity 16.9% 15.4% 17.4% Persistent hepatorenal syndrome 7.6% 7.7% 7.6% Others 4.2% 7.7% 3.3% RIFLE criteria c Risk 23.7% 3.8% 29.3% Injury 51.7% 69.2% 46.7% Failure 18.6% 19.2% 18.5% Loss 5.9% 7.7% 5.4% Posttransplant haemodialysis or haemofiltration 3.2% 2.8% 3.3% Deceased donor 23.0% 12.5% 25.1% Underlying disease HBV infection 79.6% 77.8% 79.9% HCV infection 3.9% 9.7% 2.8% Alcoholic liver disease 4.9% 4.2% 5.0% Others 11.6% 8.3% 12.3% HBV viraemia at transplantation d 82.3% 77.4% 83.0% HBV viraemia after transplantation d 8.1% 15.2% 6.8% Anti-HBV therapy d None used 9.8% 23.2% 7.3% Lamivudine 66.8% 71.4% 65.9% Lamivudine adefovir 4.4% 1.8% 4.9% Adefovir 4.4% 0.0% 5.2% Entecavir 14.6% 3.6% 16.7% Hepatocellular carcinoma 39.9% 43.1% 39.3% Child Pugh score 10.6 ± ± ± MELD score 21.0 ± ± ± Inhibitors of purine synthesis 0.001 None used 56.1% 13.9% 64.6% Mycophenolate 43.4% 83.3% 35.4% Azathioprine 0.5% 2.8% 0.0% Trough level of CNIs (ng/ml) [% of patients with trough levels above the target range e ] Posttransplant 1 month ± 75.1 [8.6%] 10.0 ± 2.5 [9.6%] f Posttransplant 3 months ± 62.3 [1.4%] 8.5 ± 2.2 [2.9%] f Posttransplant 6 months ± 50.4 [15.4%] 6.8 ± 2.2 [6.9%] f Posttransplant 12 months ± 53.0 [1.5%] 5.4 ± 1.9 [1.7%] f Mean ± SD, P-value (cyclosporine vs. tacrolimus), independent t-test for continuous variables and chi-squared test or Fisher s exact test for categorical variable. egfr, estimated glomerular filtration rate by MDRD formula; ARF, acute renal failure; HBV, hepatitis B virus; HCV, hepatitis C virus. a In the recipients with pretransplant diabetes mellitus. b In the recipients with pretransplant hypertension. c In the posttransplant ARF(+) recipients. d In the HBV recipients. e Target range of cyclosporine: ng/ml at 1 and 3 months, ng/ml at 6 and 12 months; target range of tacrolimus: 8 13 ng/ml at 1 and 3 months, 5 10 ng/ml at 6 and 12 months. f Fisher s exact test. CKD after liver transplantation 2775 2776 J.P. Lee et al. Table 2. Univariate and multivariate analyses of the hazard ratios for chronic kidney disease (egfr 60 ml/min/1.73 m 2 ) after liver transplantation in all recipients Univariate Cox regression Multivariate Cox regression a HR (95% CI) P-value HR (95% CI) P-value Male recipient (vs. female) 0.61 ( ) ( ) a Recipient age (years) 1.08 ( ) ( ) 0.001 a Era (referent) 1 (referent) ( ) ( ) a ( ) ( ) a Body mass index 0.98 ( ) ( ) a Pretransplant diabetes mellitus 1.98 ( ) ( ) a Duration of diabetes (years) d 1.03 ( ) ( ) a Duration of treated diabetes (years) d 1.03 ( ) ( ) a Pretransplant hypertension 2.09 ( ) ( ) a Duration of anti-hypertensive therapy (years) 0.97 ( ) (0.00 ) a History of cardiovascular disease 1.86 ( ) ( ) a Deceased donor (vs. living donor) 0.95 ( ) ( ) a Underlying disease HBV infection 1 (referent) 1 (referent) HCV infection 2.39 ( ) ( ) a Alcoholic liver disease 0.76 ( ) ( ) a Others 1.09 ( ) ( ) a HBV-related liver disease (vs. non-hbv-related disease) 0.81 ( ) ( ) b Hepatocellular carcinoma 0.88 ( ) ( ) a Use of adefovir 1.01 ( ) ( ) a Calcineurin inhibitor Tacrolimus 1 (referent) 1 (referent) Cyclosporine 2.22 ( ) ( ) a Inhibitors of purine metabolism None used 1 (referent) 1 (referent) Mycophenolate mofetil 1.81 ( ) ( ) a Azathioprine 1.14 ( ) ( ) a Acute rejection 1.44 ( ) ( ) a Posttransplant ARF (vs. no ARF) 1.46 ( ) ( ) a Cause of ARF No ARF 1 (referent) 1 (referent) Ischaemic ATN 1.66 ( ) ( ) c Prerenal ARF 0.48 ( ) ( ) c CNIs toxicity 2.98 ( ) ( ) 0.001 c Persistent hepatorenal syndrome 6.81 ( ) ( ) c RIFLE criteria No ARF 1 (referent) 1 (referent) Risk 0.99 ( ) ( ) c Injury 1.81 ( ) ( ) c Failure 1.55 ( ) ( ) c Loss 2.70 ( ) ( ) c Pretransplant haemoglobin (g/dl) 0.86 ( ) ( ) a Pretransplant egfr (ml/min/1.73 m 2 ) 0.97 ( ) ( ) 0.001 a Pretransplant proteinuria 2.32 ( ) ( ) a Hepatorenal syndrome 5.67 ( ) ( ) 0.001 d Child Pugh score 1.13 ( ) ( ) a MELD score 1.05 ( ) ( ) 0.001 e HR, hazard ratio; ARF, acute renal failure; egfr, estimated glomerular filtration rate by MDRD formula; MELD, Model for End-Stage Liver Disease. a Adjusted for the following variables: recipient age, gender, pretransplant diabetes mellitus, pretransplant hypertension, underlying disease, calcineurin inhibitor, inhibitors of purine metabolism, posttransplant ARF, pretransplant haemoglobin, pretransplant egfr, pretransplant proteinuria and Child Pugh score. b Adjusted for the variables listed in footnote (a) except for underlying disease. c Adjusted for the variables listed in footnote (a) except for posttransplant ARF. d Adjusted for the variables listed in footnote (a) except for pretransplant egfr. e Adjusted for the variables listed in footnote (a) except for pretransplant egfr and Child Pugh score. Fig. 1. Kidney function after liver transplantation and incidence of CKD. (A) Overall egfr after liver transplantation (paired t-test, *P 0.05). (B) Cumulative incidence of CKD (egfr 60 ml/min/1.73 m 2 ). (C) Cumulative incidence of severe CKD (egfr 30 ml/min/1.73 m 2 ). CKD after liver transplantation 2777 Fig. 2. Relationship between posttransplant ARF and CKD. Cumulative incidence of CKD (egfr 60 ml/min/1.73 m 2 ) according to (A) causes of posttransplant ARF (log-rank test, *P 0.05; **P 0.001) and (B) RIFLE criteria of posttransplant ARF (log-rank test, **P 0.01). 2778 J.P. Lee et al. Fig. 3. Impact of pretransplant egfr and progression of CKD. Kidney function at sequential time points in comparison to the pretransplant egfr (mean ± SD, paired t-test, *P 0.05); pre-tx, pretransplant. jections were found in 9.2% of patients. The proportion of patients with hepatorenal syndrome was 12.1%. The mean Child Pugh and MELD scores (±SD) were 10.6 ± 2.6 and 21.0 ± 10.0, respectively. Posttransplantation ARF was documented in 27.4% of the recipients. The most common cause was ischaemic ATN (44.1%), followed by prerenal ARF (27.1%) and CNI nephrotoxicity (16.9%). Fourteen recipients (3.2%) had ARF of sufficient severity as to require renal replacement therapy after liver transplant surgery. Twenty-three (5.3%) deaths were observed during the follow-up period. The causes of death were as follows: 8 from infection, 10 from recurrence of hepatocellular carcinoma, 4 from hepatic failure due to rejection and 1 from cardiovascular disease. Kidney function after liver transplantation and incidence of chronic kidney disease The mean egfr (ml/min/1.73 m 2,±SD)was82± 30.0 ml/min/1.73 m 2 before transpl
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