Introduction: The clinical importance of humoral-mediated acute rejection has been progressively recognised. Early recognition and treatment with plasmapheresis and intravenous immunoglobulin have recently improved short term prognosis.
Case report: In this report we describe the
clinical features of three 2nd transplant patients developing severe acute humoral rejection during the first week post-transplant while on anti-thymocyte globulin therapy. Treatment with plasmapheresis/
intravenous immunoglobulin/rituximab resulted in rapid reversal of oliguria,and recovery of renal function within the 1st week of treatment in 2/3 patients. Diagnosis was confirmed by graft biopsies revealing peritubular neutrophiles and C4d deposits.
Sequential graft biopsies in all three patients revealed complete histological recovery within two weeks. One patient never recovered renal function, and one patient lost his graft at three months following hemorrhagic shock. After 2 years follow up, the remaining patient maintains a serum creatinine of 1.1mg/dl.
Conclusion: The regimen using plasmapheresis
plus intravenous immunoglobulin and rituximab was effective in rapidly reversing severe
acute humoral rejection

Barber, E

Barroso, E

Carvalho, F

Domingos, M

Manuel, F

Nolasco, F

Pessegueiro, P

Possante, M

Reimão Pinto, J

Ribeiro Santos, J

Sampaio, S

Sousa, J

Viana, H

Repository of the Hospital Center of Central Lisbon

Triple Regimen with Rituximab, Plasmapheresis and Intravenous Immunoglobulin in the Treatment of Dialysis Dependent Acute Humoral-Mediated Rejection in Kidney Grafts

Repositório do Centro Hospitalar de Lisboa Central, EPE

Revista Portuguesa de Nefrologia e Hipertensão 131TRIPLE REGIMEN WITH RITUXIMAB, PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULIN IN THETREATMENT OF DIALYSIS DEPENDENT ACUTE HUMORAL-MEDIATED REJECTION IN KIDNEY GRAFTSRev Port Nefrol Hipert 2006; 20 (2): 131-135ABSTRACTIntroduction: The clinical importance of hu-moral-mediated acute rejection has been pro-gressively recognised. Early recognition andtreatment with plasmapheresis and intravenousimmunoglobulin have recently improved shortterm prognosis.Case report: In this report we describe theclinical features of three 2nd transplant patientsdeveloping severe acute humoral rejection dur-ing the first week post-transplant while on anti-Triple regimen with rituximab,plasmapheresis and intravenousimmunoglobulin in the treatment of dialysisdependent acute humoral-mediated rejectionin kidney graftsPedro Pessegueiro1, Fernando Nolasco2,3, Sandra Sampaio4, Fernanda Carvalho3Felicidade Manuel2,3, Engrácia Barber2,3, Helena Viana2,3, João Sousa2,3,Marília Possante2,3, Margarida Domingos2,3, José Reimão Pinto2,3,João Ribeiro Santos2,3, Eduardo Barroso21 Unidade de Nefrologia, Hospital Espírito Santo, Évora2 Unidade de Transplante, Hospital Curry Cabral, Lisboa3 Serviço de Nefrologia, Hospital Curry Cabral, Lisboa4 Serviço de Nefrologia, Hospital Distrital de Faro, FaroCase ReportReceived for publication: 16/09/2005Accepted in revised form: 07/02/2006thymocyte globulin therapy. Treatment with plas-mapheresis/intravenous immunoglobulin/rituximab resulted in rapid reversal of oliguria,and recovery of renal function within the 1st weekof treatment in 2/3 patients. Diagnosis was con-firmed by graft biopsies revealing peritubularneutrophiles and C4d deposits.Sequential graft biopsies in all three patientsrevealed complete histological recovery withintwo weeks. One patient never recovered renalfunction, and one patient lost his graft at threemonths following hemorrhagic shock. After 2years follow up, the remaining patient maintainsa serum creatinine of 1.1mg/dl.Conclusion: The regimen using plasmaphe-resis plus intravenous immunoglobulin andrituximab was effective in rapidly reversing se-vere acute humoral rejection.Key-Words: Acute humoral-mediated rejection;kidney transplant; plasmapheresis; rituximab.INTRODUCTIONThe importance and clinical significance ofhumoral alloimmunity in renal transplant (Tx) iscurrently under re-evaluation.Acute humoral rejection (AHR) seems moreprevalent than previously thought, with a preva-lence of 5% to 7%, increasing to 20-30% in casesof biopsy performed for acute rejection1.The criteria for diagnosis of AHR have recentlybeen established2,3: 1) evidence of clinical graftdisfunction, 2) histologic evidence of tissue in-jury (neutrophil margination in the peritubularcapillaries, acute tubular injury, fibrinoid necro-sis), 3) immunopathological evidence for anti-body (C4d positive staining in the peritubullarcapilaries or Ig/C3 deposition in arteries) 4) andserological evidence of anti-donor antibodies attime of biopsy.Prognosis for AHR varies, depending on theseverity of clinical/histological lesions, and timingof treatment.In this report we describe the prompt reco-very of two out of three patients with severe AHR,developed under treatment with anti-thymocytegobulin (ATG)/tacrolimus/micophenolate mofetil,and rapidly recovering after treatment with plas-mapheresis (PMF), intravenous immunoglobu-lin (IVIG) and rituximab.CASE REPORTThe authors describe the clinical features ofthree kidney transplanted patients all receivinga 2nd kidney graft developing severe AHR (TableI). All were presensitized patients, two with >75%panel-reactive antibodies. Protocol inductiontherapy included ATG (2mg/kg/day; 10 days),tacrolimus (0.07mg/Kg/day increasing to 0.2mg/Kg/day by 7th day) plus mycophenolate mophetil(MMF; 500mg/day increasing to 2g/day) plusprednisolone (20mg/day).Patient A received his second renal transplantfrom a cadaver donor (20% glomerular sclero-sis on the donor kidney biopsy), and had a pre-Txweakly positive HLA-II cytometric flux crossmatch(FCC), unknown at the time of transplant. He wasanuric and required haemodialysis.Patient B received a second kidney allograftfrom a cadaver donor, and although presentinga pre-Tx negative FCC he had a historical posi-tive control (Table II). After Tx, a rapid recoveryof renal function was attained, with serum crea-tinine reaching 2.0 mg/dl at the 5th day. 48 hoursafter, low grade fever, rapid decrease in diuresisand renal function were observed, leading to ur-gent haemodialysis.Patient C, hepatitis C virus positive, receivedhis second kidney transplant from a cadaverdonor (presenting an anatomical abnormality:two small renal arteries). Although pre-Txcitotoxic crossmatch was negative, FCC turnedout slightly positive (Table II). After an initial slightrecovery of renal function until the 4th day post-Tx., low grade fever appeared, and a rapid de-crease in urinary output occurred which lead toinduction of dialysis at the 7th day.Blood cultures returned negative and allograftecodoppler was normal in all three patients.All three patients underwent graft biopsy andthis showed the presence of neutrophiles in theperitubular capillaries and a imunofluorescenceRevista Portuguesa de Nefrologia e Hipertensão132Pedro Pessegueiro, Fernando Nolasco, Sandra Sampaio, Fernanda Carvalho, Felicidade Manuel,Engrácia Barber, Helena Viana, João Sousa, Marília Possante, Margarida Domingos, José Reimão Pinto,João Ribeiro Santos, Eduardo BarrosoC4d positive result. Severe AHR was diagnosed(Figure 1).All patients were treated with 5 daily PMFsessions (one plasma volume exchange), IVIG(400mg/kg) after each PMF, repeated once af-ter 21 days, plus one or two (21 days apart) ad-ministrations of rituximab (375 mg/m2).Three days after initiating this regimen, 2/3patients presented a rapid increase in diuresis,with a steady recovery of renal function (patient A:creatinine 1.9mg/dl at day 50; patient B: creati-nine 1.1mg/dl at day 90). Patient C remainedanuric, dialysis-dependent.Post-treatment graft biopsies showed a com-plete resolution of the AHR features in all pa-tients. However, patient A still showed donorsevere chronic lesions and patient C showedpresence of ischemic glomeruli.Although all patients attained resolution of theAHR, two of them lost permanently their graftfunction. Patient A, while partly recovering renalfunction (minimal serum creatinine of 1.9mg/dleven after an episode of acute celular rejectionBANF IA), eventually had his graft removed as aconsequence of multiple surgical complications(infected volumous linfocele, life-threateninghaemorrhage after a graft biopsy). Patient Ccontinued to show ischemic glomerular lesions,and further investigation revealed a high pres-sure arteriovenous shunt as the cause of de-creased diastolic blood flow. Even after AV shuntremoval, no renal recovery was observed.In conclusion, the treatment regimen usedallowed 100% resolution of severe AHR and al-though only 33% of graft survival was attained,no graft loss was directly caused by humoralrejection, but by haemodynamic complications.Moreover, all patients saw their initial histologi-cal abnormalities completely resolved.During follow up of the remaining patient (B)with functioning allograft, a cutaneous-born sys-temic infection by Alternaria spp fungus was dia-gnosed. It was  treated with long term anti-my-cotic therapy. No other severe complication wasTable I - Patient’s outlined characteristics* Rejection occurred at 3 months after transplant; A/G/R: age/gender (Male, Fe-male)/race (Caucasian, Black); CRF: chronic renal failure; IgAN: ImmunoglobulinA nephropathy; HNAS: Hypertensive nephroangiosclerosis; Tx: transplantAcute hummoral mediated rejection. Presence of neutrophiles inthe peritubular capillaries (arrows) and pericapillariesimunofluorescence C4d positive stain. Acute tubular necrosisalso observed. IMF: immunofluorescence; H&E: hematoxylinand eosin staining.Table II - Crossmatch and panel-reactive antibodies monitoringfeaturesTx: transplant; Tr: treatment; FCC: flux citometry crossmatch; PRA: panel-reac-tive antibodies; PCr: plasma creatinine; I: HLA antigens class I (normal values<200UI); II: HLA antigens class II (normal values <250UI)Figure 1PatientABCA/G/R44/M/C40/M/C50/M/BCRF actiologyIgANHNASHNASLoss of previousd TxChronic rejectionSHUUnknown*Mismatch432398 (I)130 (II)141 (I)260 (II)158 (I)135 (II)220 (I)725 (II)17% (I)63% (II)96% (I)0% (II)71% (I)99% (II)503 (I)425 (II)7733 (I)2268 (II)4691 (I)2736 (II)83% (II)99% (I)0% (II)71% (I)99% (II)241 (I)2915 (II)289 (I)772 (II)667 (I)3504 (II)41% (II)97% (I)0% (II)92% (I)91% (II)HD1.1mg/dlHDHistoricalFCC (UI)Pre TxFCC (UI)Pre TxPRA (%)Post TxFCC (UI)Post TxPRA (%)Post TrFCC (UI)Post TrPRA (%)PCr after2 yearsPatientABCRevista Portuguesa de Nefrologia e Hipertensão 133TRIPLE REGIMEN WITH RITUXIMAB, PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULIN IN THETREATMENT OF DIALYSIS DEPENDENT ACUTE HUMORAL-MEDIATED REJECTION IN KIDNEY GRAFTSRevista Portuguesa de Nefrologia e Hipertensão134Pedro Pessegueiro, Fernando Nolasco, Sandra Sampaio, Fernanda Carvalho, Felicidade Manuel,Engrácia Barber, Helena Viana, João Sousa, Marília Possante, Margarida Domingos, José Reimão Pinto,João Ribeiro Santos, Eduardo Barrosonoticed, allowing, after 24 months, a plasma cre-atinine level of 1.1mg/dl (Table II).DISCUSSIONOver the last 40 years, most clinical and re-search emphasis has been on the cellular as-pects of allograft rejection. It is only recently thatthere has been more emphasis on the antibody-mediated injury, due to the development of a newdiagnostic technique, C4d staining4,5. Thisshowed that AHR is more prevalent than previ-ously considered6, and that these patients seemto have worse prognosis, with an increased rateof early graft loss and an early and increasedprogression to chronic graft dysfunction7-10.Crespo et al1 have shown that the presenceof C4d correlates very well with the presence ofanti-donor specific antibodies in the serum.These anti-HLA antibodies can be rather nonspecific, being directed mostly against class I1.The antibodies are mainly IgG, produced byplasma cells. These cells represent the goal interms of inhibiting antibody production.Controversy stills reigns over how best to treatthese patients. Several therapies have been tried,but all with limited success, mainly due to theirinability to inhibit the antibody-producers plasmacells1,11-16. The therapies currently available areMMF, IVIG, rituximab, and removal of antibodiesby PMF.Mycophenolate acts by inhibiting B cell proli-feration, mostly by reducing expression of mo-lecules responsible for B cell activation and sur-vival. It therefore inhibits de novo immuneresponses, having a negligible effect in terms ofinhibiting antibodies that already exist.IVIG is effective in reducing anti-HLA antibo-dies in sensitized patients12. It is also effectivein treating mild AHR12,17. However, it is expen-sive, has significant side effects, and is non-spe-cific. IVIG efficacy appears to be mainly due tomechanisms such as an anti-idiotypic antibodyeffect and inhibition of the B cell activation12,17.Rituximab is a chimeric antibody directedagainst CD20, which is only expressed on rest-ing and activated B cells, not on plasma cells.With the isolated use of this drug, antibody pro-duction by plasma cells is maintained, but a de-crease in de novo antibody production occursand, by clearing B cells, it also clears B cellsantigen-presenting function. Its role seems li-mited to maintaining a low level of production ofdonor antibodies after gross removal has beenattained, suggesting a possible role in prevent-ing further AHR episodes.The triple therapeutic regimen using PMF, IVIGand rituximab seems effective in treating the se-vere AHR14. Not only was a significant reductionin the anti-donor antibodies levels observed, butalso a complete return to normal of the histo-logical findings on graft biopsy.As in all these three patients, a higher histori-cal and pretransplant sensitization or a previousfailed allograft are known risk factors for AHR,suggesting that a humoral response against do-nor-specific antigens plays a role in thepathogenesis of this type of rejection1.Although the considered triple regimenshowed a good effect in the acute severe set-ting, its long-term effect has to be validated.Moreover, with such an intensive immunosup-pressive regimen, the infectious complicationshave become the major potential problem.Recommendations published in 200414 con-cluded that effective treatment exists to reversepost transplant AHR. While high IVIG pulses(1-2g/kg) or plasmapheresis plus low dose IVIGmodalities have proven efficacy for antibody re-moval14, they have yet to be tested in rigorousprospective, multicentre studies. Rituximab orsplenectomy was also reported to increase thetreatment potency in the more severe cases14.Revista Portuguesa de Nefrologia e Hipertensão 135TRIPLE REGIMEN WITH RITUXIMAB, PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULIN IN THETREATMENT OF DIALYSIS DEPENDENT ACUTE HUMORAL-MEDIATED REJECTION IN KIDNEY GRAFTSIn conclusion, although the diagnosis of se-vere AHR requiring dialysis in patients alreadyunder ATG is usually associated with renal graftloss, it is possible to obtain complete histologi-cal recovery, and clinical improvement, by em-ploying triple therapy with PMF, IVIG andRituximab.  Prompt diagnosis and treatment isessential for such a result.Correspondence and offprint requests to:Dr. Pedro PessegueiroUnidade de Nefrologia, Hospital Espírito SantoLargo Sr. da Pobreza, 7000-811 Évora, PortugalE-mail: ppessegueiro@hotmail.comREFERENCES1. Crespo M, Pascual M, Tolkoff-Rubin N, Mauiyyedi S, CollinsAB, Fitzpatrick D, et al. Acute humoral rejection in renalallograft recipients: I. Incidence, serology and clinical cha-racteristics. Transplantation 2001;71:652-82. Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF,Campbell PM, et al. Antibody-mediated rejection criteria - anaddition to the Banff 97 classification of renal allograft re-jection. Am J Transplant 2003;3:708-143. Mauiyyedi S, Crespo M, Collins AB, Schneeberger EE,Pascual MA, Saidman SL, et al. Acute humoral rejection inkidney transplantation: II. Morphology, immunopathology, andpathologic classification. J Am Soc Nephrol 2002;13:779--874. Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch MJ. Detec-tion of the complement degradation product C4d in renalallografts: diagnostic and therapeutic implications. J Am SocNephrol 2002;13:242-515. Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies andrejection: is C4d a magic marker? Nephrol Dial Transplant2003;:2232-96. Mauiyedi S, Pelle PD, Saidman S, et al. Chronic humoralrejection: identification of antibody-mediated chronic renalallograft rejection by C4d deposits in peritubular capillaries.J Am Soc Nephrol 2001;12:574-827. Worthington JE, Martin S, Al-Husseini DM, Dyer PA, JohnsonRW. Posttransplantation production of donor HLA-specificantibodies as a predictor of renal transplant outcome. Trans-plantation 2003;75:1034-408. Herzenberg AM, Gill JS, Djurdjev O, Magil AB. C4d deposi-tion in acute rejection: an independent long-term prognosticfactor. J Am Soc Nephrol 2002;13:234-419. Gloor JM, DeGoey S, Ploeger N, et al. Persistence of lowlevels of alloantibody after desensitization in crossmatch-positive living-donor kidney transplantation. Transplantation2004;78:221-710. Regele H, Böhmig G, Habicht A, et al. Capillary deposition ofcomplement split product C4d in renal allografts is associ-ated with basement membrane injury in peritubular andglmerular capillaries: a contribution of humoral immunity tochronic allograft rejection. J Am Soc Nephrol 2002;13:2371--8011. Becker Y, Becker B, Pirsch J, Sollinger H. Rituximab astreatment for refractory kidney transplant rejection. Am JTransplantation 2004;4:996-100112. Rocha PN, Butterly DW, Greenberg A, Reddan DN, Tuttle-Newhall J, Collins BH, et al. Beneficial effect of plasmaphe-resis and intravenous immunoglobulin on renal allograft sur-vival of patients with acute humoral rejection. Transplantation2003;75:1490-513. Zachary A, Montgomery R, Ratner L, et al. Specific anddurable elimination of antibody to donor HLA antigens inrenal-transplant patients. Transplantation 2003;76:1519-2514. Takemoto S, Zeevi A, Feng S, et al. National conference toassess antibody-mediated rejection in solid organ trans-plantation. Am J Transplantation 2004;4:1033-4115. Shah A, Nadasdy T, Arend L, et al. Treatment of C4d-posi-tive acute humoral rejection with plasmapheresis and rabbitpolyclonal antithymocyte globulin. Transplantation2004;77:1399-40516. Luke P, Scantlebury V, Jordan M, et al. Reversal of steroid-and anti-lymphocyte antibody-resistant rejection using in-travenous immunoglobulin (IVIG) in renal transplant reci-pients. Transplantation 2001;72:419-2217. Casadel D, Rial M, Opelz G, et al. A randomized andprospective study comparing treatment with high-dose in-travenous immunoglobulin with monoclonal antibodies forrescue of kidney grafts with steroid-resistant rejection.Transplantation 2001;71:53-8

http://repositorio.chlc.min-saude.pt/bitstream/10400.17/2263/1/RPNH%202006%20131.pdf

Triple Regimen with Rituximab, Plasmapheresis and Intravenous Immunoglobulin in the Treatment of Dialysis Dependent Acute Humoral-Mediated Rejection in Kidney Grafts

Abstract

Similar works

Full text

Available Versions

Repository of the Hospital Center of Central Lisbon

Repositório do Centro Hospitalar de Lisboa Central, EPE