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COMPLICATIONS
he Burden of Chronic Kidney Disease in Long-Term Liverransplant Recipients
. de Boccardo, J.-Y. Kim, T.D. Schiano, R. Maurette, R. Gagliardi, B. Murphy, S. Emre, and E. Akalin
ABSTRACT
Background. Chronic kidney disease (CKD) is an important risk factor for morbidityand mortality post–liver transplantation (OLT). This study focused on investigating theincidence and risk factors associated with the development CKD after OLT.Methods. We performed a retrospective cohort study of recipients followed at least 5years at our institution. CKD was diagnosed and classified according to National KidneyFoundation and the Kidney Disease Outcomes Quality Initiative guidelines.Results. There were 231 patients, 64% men, 67% Caucasian, 16% African-American,and 17% others, with a mean age of 56 � 13 years. The mean glomerular filtration rate(GFR) of the population was 56 � 28 mL/min/1.73 m2. CKD was defined as GFR less than60 mL/min; 144 patients (61%) were identified as having CKD. When these patients werecompared to the non-CKD group, the former were significantly older (62 � 9 vs 52 � 12years, P � .03), more likely to be hypertensive (59% vs 38%, P � .003), and required moreantihypertensive medications (0.83 � 0.81 vs 0.52 � 0.77, P � .02); 26% of all patients haddiabetes. However, the incidence of diabetes (43.3% vs 19.3%, P � .02) as well as theincidence of insulin dependency (21.6% vs 12.5%, P � .001) was significantly higher in theCKD population. Mean uric acid levels were higher in CKD patients compared tonon-CKD patients (8.00 � 2.00 mg/dL vs 6.70 � 1.99 mg/dL respectively, P � .001);patients with uric acid more than 6.0 had a 1.7 risk of having CKD.Conclusions. CKD defined as GFR � 60 mL/min is highly prevalent in long-term OLTsurvivors. Older age, elevated systolic blood pressure, insulin-dependent diabetes mellitus,and elevated uric acid levels are independently associated with CKD.
From the Division of Nephrology (G.d.B., Y.-Y.K., B.M., E.A.),ecanati Miller Liver Transplantation Institute, (G.d.B., T.D.S.,.M., R.G., B.M., E.A.), and Division of Hepatology (T.D.S.), Theount Sinai School of Medicine, New York, New York, USA, and
ransplant and Immunology (S.E.), Yale University School of
Address reprint requests to Thomas Schiano, MD, MountSinai Medical Center, One Gustave L. Levy Place, Box 1104,New York, NY 10029. E-mail: [email protected]
edicine, New Haven, Connecticut, USA.
041-1345/08/$–see front matter © 2008 by Elsevier Inc. All rights reserved.oi:10.1016/j.transproceed.2008.03.099 360 Park Avenue South, New York, NY 10010-1710
498 Transplantation Proceedings, 40, 1498–1503 (2008)
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BURDEN OF CHRONIC KIDNEY DISEASE 1499
EW AND MORE POTENT immunosuppressivestrategies have led to a significant improvement in
he long-term survival of liver transplant (OLT) recipients.1
owever, despite the improvement in patient and grafturvival, there remains significant morbidity and mortalityue to recurrence of the original disease, development ofardiovascular disease (CVD), and side effects of themmunosuppressant medication.2,3 The incidence ofhronic kidney disease (CKD) reported in OLT patientsanges from 20% to 80%.4,5 This wide disparity could bettributed to either the lack of a clear definition of CKD orhe methodology utilized to estimate renal function in theseatients. The incidence of end-stage renal disease in OLTecipients is more consistent, ranging from 4.5% to 9.5% atyears.6,7 The etiology of CKD in long-term OLT recipi-
nts is probably multifactorial, but mostly attributed to theephrotoxic side effects of calcineurin inhibitors (CNI).8
owever, it should be noted that none of the previoustudies documented CNI toxicity by biopsy.9,10
In 2002, the National Kidney Foundation and the Kidneyisease Outcomes Quality Initiative (K/DOQI) classifiedKD according to the degree of renal impairment, inde-endent of the cause. CKD was defined as kidney damageith proteinuria and/or glomerular filtration rate (GFR)
ess than 60 mL/min/1.73 m2 for more than 3 months. Theseuidelines are validated and widely accepted, and advise thepplication of the Modified Diet of Renal DiseaseMDRD) equation for the calculation of GFR.11 The
DRD equation has been found to correlate well withFR as measured by an isotopic method (51Cr-EDTA) in
atients with moderate or severe renal dysfunction.12
In this retrospective cohort study, we evaluated thencidence and risk factors for the development of differenttages of CKD according to the K/DOQI guidelines intable OLT recipients with a minimum follow-up of 5 years.
ATERIALS AND METHODS
his study included all adult patients (18 years of age or older)ho received OLT at The Mount Sinai Medical Center fromanuary 1997 to December 1999. The cutoff date for our analysisas January 1, 2005. A total of 502 OLT were performed during
his period, and 284 patients (57%) were alive. Of the 284urvivors, 231 patients who were regularly followed at ourost-OLT clinic were included in the study. Preoperative vari-bles analyzed were: age, sex, race, body mass index (BMI,efined as weight in kg/height in meters squared), and cause of
iver disease. The pre-OLT history of smoking, presence orbsence of hepatorenal syndrome, hypertension (HTN), diabe-es mellitus (DM), serum creatinine, and need for renal replace-ent therapy were also evaluated. Post-OLT variables analyzedere: weight, systolic and diastolic blood pressure, number oflood pressure medications, immunosuppressive medications,osttransplant DM, and type of diabetes treatment (oral agentsr insulin). Laboratory data included: CBC, platelets, INR,UN, creatinine, AST, ALT, albumin, and cholesterol. HTNas defined as systolic blood pressure greater than 140 mm Hgn any single visit, diastolic blood pressure greater than 90 mmg on any single visit, or the use of antihypertensive medications. DM
as defined as the use of insulin or oral hypoglycemic agents. rCreatinine clearance was calculated using the MDRD equa-ion.13 CKD was classified according to the K/DOQI guidelines.11
KD stage I is defined as a GFR greater than or equal to 90L/min, stage II as a GFR between 60 mL/min and 90 mL/min,
tage III as a GFR between 30 mL/min and 60 mL/min, stage IV asGFR between 15 mL/min and 30 mL/min, and stage V CKD asGFR less than 15 mL/min. The study was reviewed and approvedy the Institutional Review Board of our institution.
tatistical Analysis
emographics and variables were analyzed using SPSS softwarend results expressed as a mean � standard deviation. The finalndpoint of the analysis was the calculation of MDRD GFR at thend of 5 years. A subsequent subanalysis was performed comparingatients with and without CKD. The two groups were comparedsing the mean and standard deviation for each variable to assessssociation with CKD. Categorical data were compared using thehi-square test. Continuous variables were compared using the test. All tests were two-tailed and a P value of less than .05 wasonsidered statistically significant. A multivariable logistic analysisere performed to assess for risk independently associated with theevelopment of CKD.
ESULTSatient Population
he median follow-up was 73 months (range, 60 to 84onths). There were 231 patients in the study and the
atient demographics are shown in Table 1. There were 147en (64%) and 84 women (36%), Caucasian (67%) andfrican-American (16%), with a mean age of 56 � 12 years.he indications for OLT were: hepatitis C virus (HCV; n �11), primary biliary cirrhosis (n � 32), alcoholic liverisease (n � 23), hepatitis B virus (n � 23), cryptogenicirrhosis (n � 16), autoimmune hepatitis (n � 10), primaryclerosing cholangitis (n � 13), and sarcoidosis (n � 3). Athe last follow-up visit, 95% of the patients were taking CNInd 13%, antiproliferative agents. Prior to OLT, 22 of theatients (9.5%) had HTN, 42 had DM (18%), 16 hadepatorenal syndrome (6.9%), and 103 had a history ofmoking (44.6%). The mean serum creatinine level beforeLT was 1.26 � 1.0 mg/dL.At the end of follow-up, the mean GFR of the total study
opulation was 56 � 28 mL/min/1.73 m2. Stage I CKD wasound in 23 patients (10%) with a mean GFR of 114 � 2L/min, stage II in 64 patients (28%) with a mean GFR of
2 � 7 mL/min, stage III in 109 patients (47%) with a meanFR of 46 � 8 mL/min, stage IV in 15 patients (6%) withmean GFR of 25 � 3 mL/min, and stage V in 20 (8%)ith a mean GFR of 10 � 2 mL/min (Table 2).Of the 231 patients, 144 (62%) had a GFR of less than 60L/min and were defined as having CKD, while 88 (38%)
ad a GFR of more than 60 mL/min. In comparing the tworoups, there were no statistically significant differences inerms of BMI, albumin and cholesterol levels, prevalence ofCV, hepatorenal syndrome (Table 3).Patients who developed CKD were significantly older at
he time of the transplant (62 � 9 years vs 52 � 12 years,
espectively). Hypertension was more commonly observed
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n CKD patients compared to non-CKD patients (59% vs9%, respectively, P � 0.003). In addition, CKD patientsad higher systolic blood pressures and required morentihypertensive medications compared to non-CKD pa-ients (0.83 vs 0.52, P � .02). The main antihypertensiveedications utilized were calcium channel blockers (60%),
ollowed by beta blockers (50%) and diuretics (20%).verall, posttransplant DM was seen in 38% of the popu-
ation, but the percentage of diabetic patients was greater inhe CKD group compared with the non-CKD group (43.3%s 19%, P � .002). In addition, the presence of diabetes
Table 1. Characteristics of the Study Population
Variable n � 231
retransplantMale 147 (63.6%)Female 84 (36.4%)Mean age (y) 56 � 12Race
White 158 (68%)Black 35 (15.2%)Asian 13 (5.6%)Others 25 (11.2%)
Height (m) 1.52 � 0.49Weight (kg) 79 � 20Body mass index 28 � 7.2Hepatitis C-positive patients 111 (48%)Hepatorenal syndrome 16 (6.9%)Pretransplant smoking 103 (44.6%)Pretransplant serum creatinine (mg/dL) 1.26 � 1.0Pretransplant hypertension 22 (9.5%)Pretransplant diabetes 42 (18%)
osttransplantMean SBP (mm Hg) 133 � 19Mean DBP (mm Hg) 82 � 10Mean uric acid (mg/dL) 7.5 � 2.1Mean cholesterol (mg/dL) 166 � 40Mean creatinine (mg/dL) 1.8 � 1.3Mean GFR (MDRD), mL/min 56 � 28Type of immunosuppression
Tacrolimus 177 (77%)Cyclosporine 43 (19%)Mycophenolate mofetil 10 (4%)Rapamycin 8 (4%)Azathioprine 11 (5%)
Posttransplant diabetes 88 (38%)
SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomer-lar filtration rate; MDRD, modified Diet of Renal Disease.
Table 2. Categorization of CKD in Study Population
Stages ofkidney disease
n � 231(%)
GFR(mL/min)
23 (10) 114 � 2064 (28) 72 � 7
109 (47) 46 � 815 (6) 25 � 320 (8) 10 � 2
eGFR, glomerular filtration rate.
equiring insulin was significantly higher in the CKD pa-ients (21.6% vs 12.5%, P � .002). Mean uric acid levelsere higher in CKD patients compared to non-CKD pa-
ients (8.00 � 2.00 vs 6.70 � 1.99 mg/dL respectively, P �001). Patient with uric acid levels greater than 6 mg/dL hadn 1.7 higher risk of CKD. Mean cholesterol levels wereigher in the CKD group than in the non-CKD group (189 �0 vs 139 � 20 mg/dL, P � .012). The risk ratio in CKDatients was significant for uric acid (relative risk [RR] �.7), insulin-dependent DM (RR � 1.4), DM (RR � 1.4),nd HTN (RR � 1.4; Table 4). In the multivariate logisticegression analysis, uric acid levels � 6.0 mg/dL, diabetes,nsulin-dependent DM, and HTN were independently as-ociated with CKD (Table 5).
ISCUSSION
n this retrospective cohort study of stable OLT patientsollowed at our center, we found a very high incidence ofKD. Although CKD is common in long-term OLT recipi-
Table 3. Characteristics of the Study Population With andWithout Chronic Kidney Disease
Variable
GFRa
less than60 mL/min/1.73
m2 (n � 143)
GFR more than60 mL/min/1.73
m2 (n � 88) P value
ge (y) 62 � 9 52 � 12 .03eight (kg) 84 � 20 81 � 15 NSMI
b30 � 5 29 � 3 NS
ean GFR (mL/min) 39 � 15 83 � 23 .001ean pretransplantcreatinine (mg/dL)
1.7 � 0.61 0.8 � 0.17 .010
TN 84 (58.7%) 31 (38.17%) .003ore than 3 BPmedications
28 (13%) 18 (8%) .005
ean SBP (mm Hg) 148 � 12 130 � 15 .004ean DBP (mm Hg) 88 � 8 77 � 10 NSverage No. of BPmeds
0.83 � 0.81 0.52 � 0.77 .02
ean blood glucose(mg/dL)
124 � 40 104 � 36 .001
TDM 62 (43.3%) 17 (19.3%) .002nsulin-dependent
PTDM50 (21.6%) 11 (12.5%) .002
ematocrit (mg/dL) 38 � 5.1 39 � 5.1 NSlbumin (mg/dL) 4.0 � 0.48 4.01 � 0.43 NSric acid (mg/dL) 8.00 � 2.01 6.70 � 1.99 .001ric acid �6 mg/dL 110 (77%) 47 (53%) .001holesterol (mg/dL) 189 � 20 139 � 20 .012CV (percentpositive)
50 44 NS
retransplant DM 70 (50%) 38 (43%) NSretransplant HTN 15 (10%) 7 (8%) NSRS (%) 5 9 NS
Abbreviations: GFR, glomerular filtration rate; BMI, body mass index; HTN,ypertension; BP, blood pressure; SBP, systolic blood pressure; DBP, diastoliclood pressure; PTDM, posttransplant diabetes mellitus; HCV, hepatitis C virus;M, diabetes mellitus; HRS, hepatorenal syndrome.aGFR in mL/min/1.73 m2 calculated using MDRD equation.bBMI using standard formula weight in kg/height in meters squared.
nts, previous studies have not clearly defined the exact
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BURDEN OF CHRONIC KIDNEY DISEASE 1501
ncidence. In our study, only 10% of OLT recipients had aFR of more than 90 mL/min, and the mean GFR for the
ntire population was 56 mL/min (stage III CKD). Hyperten-ion was significantly more prevalent in the CKD group andppeared more difficult to control. These patients had higherean systolic blood pressure levels and required a greater
umber of antihypertensive medications. While we generallybserved a high prevalence of posttransplant DM in ouropulation, far more of the patients with CKD were likely toe both diabetic and insulin-dependent. Hyperuricemia waslso found to be an independent risk factor for the develop-ent of CKD. From all the variables that were examined (age,
ex, race, BMI, smoking, history of HCV, presence of hepa-orenal syndrome, pretransplant DM, or hypertension), onlylder age was found to be significantly associated with CKD.CKD is a known risk factor for cardiovascular morbidity
nd mortality in the nontransplant setting.13 The Heartutcomes and Prevention Evaluation (HOPE) study
howed even mild renal insufficiency was a significant riskactor for a subsequent cardiovascular event.14 The Coop-rative Cardiovascular Project demonstrated that the risk ofying for patients with moderate renal insufficiency afteryocardial infarction was three times higher than that of
atients with normal renal function.15 These results sug-ested that renal insufficiency is an independent risk factoror cardiovascular disease and should be considered inddition to other traditional risk factors.16 Transplant re-ipients are at increased risk of cardiovascular disease, andhe presence of CKD appears to further increase theurden of CVD in this population. CKD is an independentredictor of overall morbidity and mortality in the renalransplant population.17
The etiology of renal dysfunction after OLT has not beenell characterized and probably is multifactorial.18 CNIave been shown to be nephrotoxic in kidney, liver, andeart transplant recipients.19 Comparison of the develop-ent of renal dysfunction in liver transplant patients
reated with either cyclosporine or tacrolimus has nothown a significant difference, despite a lower incidence ofTN in tacrolimus-treated patients.19,20 A recent study
howed significantly lower creatinine levels at 36 monthsost-OLT in patients who were treated with tacrolimusompared to cyclosporine.21 In our study, it was not possi-le to compare the two drugs since only 17% were usingyclosporine-based regimens.
HTN is a frequent complication after solid organ trans-lantation.22 Posttransplant HTN has been reported in 40%
Table 4. Risk Factors Associated with CKD
Risk factorsRelative
risk95% confidence
interval P value
ric acid �6 mg/dL 1.7 2.916–10.927 .001iabetes 1.4 1.122–1.664 .003
nsulin-dependent diabetes 1.4 1.240–1.673 .001ypertension 1.4 1.127–1.891 .001
o 70% of OLT patients.23 In kidney transplant recipients,U
TN was found to be a predictor of increased mortality andorbidity and was also associated with higher creatinine
evels.24 After lung or heart-lung transplantation, HTN is aredictor for the development of end-stage renal failure.25
TN is a known risk factor for ischemic heart disease,eripheral vascular disease, and renal failure.26 The rela-ionship between HTN and CKD was suggested by the thirdational Health and Nutrition Examination Survey
NHANES III) and the Framingham Heart Study.HANES III reported that 70% of nonhospitalized indi-
iduals in the United States with renal dysfunction (defineds a creatinine level greater than or equal to 1.6 mg/dL inen and greater than or equal to 1.4 mg/dL in women) haveTN.27 In the Framingham Study, there was also a signif-
cant association between elevated creatinine levels andTN.16,28 Consistent with previous studies, we found a high
revalence of HTN in our long-term liver transplant recip-ents, both with and without kidney disease. However, theatients with CKD appeared to have more resistant HTNhan those without CKD. This finding suggests the combi-ation of both factors may significantly increase the risk ofVD in the liver transplant populations and should bevaluated further.
Posttransplant DM is increasingly recognized as a seriousomplication of organ transplantation.29,30 In OLT recipi-nts, the cumulative incidence of PTDM may reach 30%,imilar to that reported in kidney and heart transplantatients.31 In kidney transplant recipients, the developmentf posttransplant DM was found to be a significant riskactor for the development of CVD and for decreasedatient and graft survival.32–34 Our data suggest that thereay be a similar correlation in OLT recipients. Therefore,
t may be worthwhile to aggressively treat diabetes in thisopulation, in the hope of decreasing the incidence androgression of CKD and improving overall patient survival.Recent epidemiological studies have demonstrated that
ric acid is a major and independent risk factor for theevelopment of renal disease.35 Experimental studies haveeported that hyperuricemia induces systemic hypertensionnd renal injury via a crystal-independent mechanism,nvolving renal vasoconstriction mediated by endothelialysfunction and activation of the renin-angiotensin sys-em.35 Current data strongly suggest that hyperuricemiand/or gout markedly increase the risk for hypertension andenal insufficiency. Moreno et al demonstrated that hyper-ricemia is associated with CKD in OLT recipients.36
owever, it is not clear if hyperuricemia is secondary toenal failure or contributes to the progression of kidney
Table 5. Risk Factors Associated with CKD, MultivariableAnalysis
Risk factors P value
ypertension .024iabetes .006
nsulin-dependent diabetes .001
ric acid � 6 mg/dL .001
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1502 de BOCCARDO, KIM, SCHIANO ET AL
isease. The patients with CKD in this study had higher uriccid levels, but the significance of this finding cannot belearly determined and additional studies are required tolearly elucidate the causal relationship between hyperuri-emia and CKD.
The association of CKD with male gender, older recipi-nt age, prolonged surgery time, pretransplant hepatorenalyndrome, and posttransplant acute renal failure has beenreviously reported.37–39 However, we found no associationetween hepatorenal syndrome and CKD in this study.ince mortality was not part of our analysis, we are unableo analyze the impact that pretransplant hepatorenal syn-rome or renal dysfunction could have had on patienturvival. One limitation to our study is that our analysis mayave been biased toward the selection of healthier patientsith better long-term survival, which may have decreased
he effect of variables such as pretransplant renal dysfunc-ion.
In conclusion, we found that CKD as defined by the/DOQI guidelines is highly prevalent in long-term liver
ransplant survivors. These patients also have a high inci-ence of HTN and posttransplant DM and have higherean cholesterol levels. By multivariate analysis, insulin-
ependent DM, elevated uric acid levels, and increasedholesterol were significantly associated with the develop-ent of CKD. It is important to note that the timely
dentification and treatment of risk factors for the develop-ent of CKD could potentially increase both patient sur-
ival and decrease the development of posttransplantVD.40
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