To examine the association between HCV infection and the occurrence of post-transplant diabetes mellitus (PTDM) among renal transplant patients.
Design
Meta-analysis of observational studies.
Data Sources
We retrieved studies published in any language by systematically searching Medline, and Embase and by manually examining the references of the original articles, reviews, and monographs retrieved.
Review Methods
We included cohort and case-control studies reporting relative risk estimates and 95% confidence intervals (CIs) for PTDM occurrence with HCV after renal transplantation. Thirteen studies providing information on a total of 30,099 unique patients were included in our meta-analysis.
Results
Study-specific relative risks were weighted by the inverse of their variance to obtain fixed- and random-effects pooled estimates. The pooled relative risk (RR) for PTDM after RT was 2.73 with a 95% confidence interval (CI) of 1.94; 3.83 (10 studies). In a stratified analysis including only large studies (2 studies), the pooled RR was 1.36 (95% CI, 1.21; 1.54). Egger's regression test showed some evidence of publication bias (p=0.0001), but our sensitivity analysis showed that this issue did not meaningfully change the results.
Conclusions
Our study shows a marked increase of the risk of post-transplant diabetes mellitus in anti-hepatitis C virus-positive renal transplant recipients. The excess risk of death in hepatitis C virus-positive renal transplant recipients may be at least partially attributed to post-transplant diabetes mellitus with its attendant complications.
VosnidesG.G.. Nephrology Forum: Hepatitis C in renal transplantation.Kidney Int1997; 52: 843–61.
2.
FabriziF., MartinP., DixitV., BunnapradistS., DulaiG.. Hepatitis C virus antibody and survival after renal transplantation: Meta-analysis of observational studies.Am J Transplant2005; 5: 1452–61.
3.
MathurinP., MouquetC., PoynardT., SyllaC., BenaliaH., FretzC., ThibaultV., CadranelJ.F., BernardB., OpolonP., CoriatP., BitkerM.O.. Impact of hepatitis B and C virus on kidney transplantation outcome.Hepatology1999; 65: 667–70.
4.
CruzadoJ.M., CarreraM., TorrasJ., GrinyoJ.M.. Hepatitis C virus infection and de novo glomerular lesions in renal allografts.Am J Transplant2001; 1: 171–8.
5.
FabriziF., MartinP., DixitV., BunnapradistS., KanwalF., DulaiG.. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: Meta-analysis of clinical studies.Am J Transplant2005; 5: 2433–40.
6.
MalufD.G., FisherR.A., KingA.L., GibneyE.M., MasV.R., CotterellA.H., ShiffmanM.L., SterlingR.K., BehnkeM., PosnerM.P.. Hepatitis C virus infection and kidney transplantation: predictors of patient and graft survival.Transplantation2007; 83: 853–7.
7.
MehtaS.H., BrancatiF.L., SulkowskiM.A., StrathdeeS.A., SzkloM., ThomasD.L.. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States.Ann Intern Med2000; 133: 592–9.
8.
Delgado-BorregoA., CassonD., SchoenfeldD., SomsoukM., TerellaA., JordanS.H., BhanA., BaidS., CosimiA.B., PascualM., ChungR.T.. Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation.Transplantation2004; 77: 703–10.
9.
ZeinN.N., AbdulkarimA.S., WiesnerR.H., EganK.S., PersingD.H.. Prevalence of diabetes mellitus in patients with endstage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease.J Hepatol2000; 32: 209–14.
10.
SalibaF., LakehalM., PageuxG.P., RocheB., VanlemmensC., DuvouxC., DumortierJ., SalamèE., CalmusY., MaugendreD., and the Diapason Study Group. Risk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis C infection: An observational multicenter study.Liver Transplant2007; 13: 136–44.
11.
Gonzalez-PosadaJ.M., HernandezD., GenisB.B., PerezJ.G., Rivero SanchezM.. Impact of diabetes mellitus on kidney transplant recipients in Spain.Nephrol Dial Transplant2004; 19(Suppl): S57–61.
MontoriV.M., BasuA., ErwinP.J., VelosaJ.A., GabrielS.E., KudvaY.C.. Posttransplantation diabetes. A systematic review of the literature.Diabetes Care2002; 25: 583–92.
14.
ShintaniY., FujieH., MiyoshiH., TsutsumiT., TsukamotoK., KimuraK., KoikeK.. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance.Gastroenterology2004; 126: 840–8.
15.
StroupD.F., BerlinJ.A., MortonS.C., OlkinI., WilliamsonG.D., RennieD., MoherD., BeckerB.J., SipeT.A., ThackerS.B.. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.JAMA2000; 283: 2008–12.
16.
PoynardT., ConnH.O.. The retrieval of randomised clinical trials in liver diseases from the medical literature: A comparison of Medlars and manual methods.Control Clin Trials1985; 6: 271–9.
17.
SulancE., LaneJ.T., PumalaS.E., GroggelG.C., WrenshallL.E., StevensR.B.. New-onset diabetes after kidney transplantation: An application of 2003 International Guidelines.Transplantation2005; 80: 945–52.
18.
BhuttaA.T., ClevesM.A., CaseyP.H., CradockM.M., AnandK.J.. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis.JAMA2002; 288: 728–37.
19.
BlandJ.M., AltmanD.G.. Statistical method for assessing agreement between two methods of clinical measurement.Lancet1986; 1: 307–10.
20.
DerSimonianR., LairdN.. Meta-analysis in clinical trials.Control Clin Trials1986; 7: 177–88.
21.
TakkoucheB., Cadarso-SuarezC., SpiegelmanD.. Evaluation of old and new tests for heterogeneity in epidemiologic meta-analysis.Am J Epidemiol1999; 150: 206–15.
22.
EggerM., Davey SmithG., SchneiderM., MinderC.. Bias in meta-analysis detected by a simple, graphical test.Br Med J1997; 315: 629–34.
23.
Costa-BouzasJ., TakkoucheB., Cadarso-SuarezC., SpiegelmanD.. HEpiMA: software for the identification of heterogeneity in meta-analysis.Comput Methods Programs Biomed2001; 64: 101–7.
24.
YildizA., TutuncuY., YaziciH., AkkayaV., KayacanS.M., SeverM.S., CarinM., KarsidagK.. Association between hepatitis C virus infection and development of posttransplant diabetes mellitus in renal transplant recipients.Transplantation2002; 74: 1109–13.
25.
HirakauvaE.Y., FerrazM.L.G., PerezR.M., FerreiraA.S., SilvaA.E., HauacheO., PestanaJ.O.M.. Prevalence of diabetes mellitus in renal transplant patients with hepatitis B or C virus infection.Transplant Proc2002; 34: 3220–2.
26.
BloomR.D., RaoV., WengF., GrossmanR.A., CohenD., MangeK.C.. Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus.J Am Soc Nephrol2002; 13: 1374–80.
27.
GentilM.A., LunaE., Rodriguez-AlgarraG., OsunaA., Gonzalez-MolinaM., MazuecosA., CuberoJ.J., del CastilloD.. Incidence of diabetes mellitus requiring insulin treatment after renal transplantation in patients with hepatitis C.Nephrol Dial Transplant2002; 17: 887–91.
28.
BaidS., Tolkoff-RubinN., FarrellM.L., DemonicoF.L., WilliamsW.W., HaydenD., KoD., CosimiA.B., PascualM.. Tacrolimus-associated posttransplant diabetes mellitus in renal transplant recipients: Role of hepatitis C infection.Transplant Proc2002; 34: 1771–3.
29.
GentilM.A., LopezM., Gonzalez-RonceroF., Rodriguez-AlgarraG., PereiraP., LopezR., MartinezM., ToroJ., MateosJ.. Hepatitis C and the incidence of diabetes mellitus after renal transplant: Influence of new immunosuppression protocols.Transplant Proc2003; 35: 1748–50.
30.
KasiskeB.L., SnyderJ.J., GilbertsonD., MatasA.J.. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant2003; 3: 178–85.
31.
Lopez HidalgoR., GentilM.A., AcostaD., EscobarM.J., Sanchez IbanezF., AstorgaR.. [Association between diabetes mellitus and hepatitis C in kidney transplant patients].Nefrologia2004; 6: 572–8.
32.
GourishankarS., JhangriG.S., TonelliM., WalesL.H., CockfieldS.M.. Development of diabetes mellitus following kidney transplantation: A Canadian experience.Am J Transplant2004; 4: 1876–82.
33.
RodrigoE., de CosM.A., Fernandez-FresnedoG., SanchezB., RuizJ.C., PineraC., PalomarR., CotorrueloJ.G., Gomez-AlamilloC., Sanz de CastroS., De FranciscoA.L.M., AriasM.. Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus.Transplant Proc2005; 37: 3819–20.
34.
SezerS., BilgicA., UyarM., AratZ., OzdemirF.N., HaberalM.. Risk factors for development of posttransplant diabetes mellitus in renal transplant recipients.Transplant Proc2006; 38: 529–32.
35.
ShahT., KasraviA., HuangE., HayashiR., YoungB., ChoY.W., BunnapradistS.. Risk factors for development of new-onset diabetes mellitus after kidney transplantation.Transplantation2006; 82: 1673–6.
36.
KamarN., MariatC., DelahousseM., DentalJ., Al NajjarA., CassutoE., LefrancoisN., CointaultO., TouchardG., VillemainF., Di GiambattistaF., BenhamouP.Y.. Diabetes mellitus after kidney transplantation: a French multicentre observational study.Nephrol Dial Transplant2007; 22: 1896–1993.
37.
GentilM.A., RochaJ.L., PereiraP., AlgarraG.R., LopezR.. High incidence of diabetes mellitus after kidney transplant in patients with hepatitis C.Nephron1999; 82: 85.
38.
KamarN., MariatC., DelahousseM., LefrancoisN., DantalJ., BenhamouP., on behalf of the Diapason Study Group. New onset diabetes mellitus incidence and risk factors in kidney transplantation: Results of the observational cross-sectional study Diapason.Transplant Proc2006; 38: 2295–7.
MarcenR., MoralesJ.M., del CastilloD., CampistolJ.M., SeronD., ValdesF., AnayaF., AndresA., AriasM., BustamanteJ., CapdevilaL., EscuinF., Gil-VernetS., Gonzalez-MolinaM., LampreaveI., OppenheimerF., PallardoL., for the Spanish Renal Forum. Posttransplant diabetes mellitus in renal allograft recipients: A prospective multicenter study at 2 years.Transplant Proc2006; 38: 3530–2.
41.
AbbottK.C., LentineK.L., BucciJ.R., AgodoaL.Y., KoffJ.M., HoltzmullerK.C., SchnitzlerM.A.. Impact of diabetes mellitus and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus.J Am Soc Nephrol2004; 15: 3166–74.
42.
AbbottK.C., BernetV.J., AgodoaL.Y., YuanC.M.. Differing manifestations of hepatitis C and tacrolimus on hospitalized diabetes mellitus occurring after kidney transplantation.Ann Epidemiol2005; 15: 558–63.
43.
KonradT., ZeuzemS., ViciniP., ToffoloG., BriemD., LormannJ., HerrmannG., BergerA., KustererK., TeuberG., CobelliC., UsadelK.H.. Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interpheron alpha.Eur J Clin Invest2000; 30: 111–21.
44.
NaritaR., AbeS., KiharaY., AkiyamaT., TabaruA., OtsukiM.. Insulin resistance and insulin secretion in chronic hepatitis C virus infection.J Hepatol2004; 41: 132–8.
45.
AytugS., ReichD., SapiroL.E., BernsteinD., BegumN.. Impaired IRS-1/P13-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes.Hepatology2003; 38: 1384–92.
46.
KawaguchiT., YoshidaT., HaradaM., HisamotoT., NagaoY., IdeT., TaniguchiE., KumamuraH., HanadaS., MaeyamaM., BabaS., KogaH., KumashiroR., UenoT., OgataH., YoshimuraA., SataM.. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through upregulation of suppressor cytokine signaling 3.Am J Pathol2004; 165: 1499–1508.
47.
LaskusT., RadkowkiM., WangL., VargasH., RakelaJ.. Search for hepatitis C virus replication sites in patients with acquired immune deficiency syndrome: specific detection of negative-strand viral RNA in various tissues.Hepatology1998; 28: 1398–1401.
48.
DavilaJ.A., MorganR.O., ShaibY., McGlynnK.A., El-SaregH.B.. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.Gut2005; 54: 533–9.
49.
Romero-GomezM., Del Mar ViloriaM., AndradeR.J., SalmeronJ., DiagoM., Fernandez-RodriguezC.M., CorpasR., CruzM., GrandeL., VazquezL., Munoz-de-RuedaP., Lopez-SerranoP., GilaA., GutierrezM.L., PerezC., Ruiz-ExtremeraA., SuarezE., CastilloJ.. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients.Gastroenterology2005; 128: 636–41.
50.
MuzziA., LeandroG., Rubbia-BrandtL., JamesR., KeiserO., MalinverniR., DufourJ.F., HelblingB., HadengueA., GonversJ.J., MullhauptB., CernyA., MondelliM.U., NegroF., and the Swiss Hepatitis C Cohort Study. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients.J Hepatol2005; 42: 41–6.
