Presentation on theme: "Recurrent And De Novo GN After Renal Transplantation"— Presentation transcript:
1 Recurrent And De Novo GN After Renal Transplantation
2 Introduction The 1 year kidney allograft survival rate has improved dramatically during the last decadewith the introduction of newer IS agentsDevelopment and progression of recurrent andde novo disease does not seem to have beeninfluenced by the use of those agents
3 Introduction Clinically, recurrent GN manifests primarily as an increase in proteinuria in the allograft, usuallyassociated with progressive loss of renal functionor chronic kidney disease (CKD).
4 Introduction 30- 50 % of KT recipients have GN as the underlying cause of their ESRDThose patients are at risk of the recurrence oftheir original disease.
5 Introduction Among these patients, more than 40% develop significant proteinuria, and around 15% developpersistent nephrotic syndromeThe most common cause of post transplantationproteinuria is chronic allograft nephropathy(50%), followed by recurrent (15%) and de novo(10%) glomerulonephritis
6 Introduction Persistent proteinurea is associated with a significantly reduced rate of graft survival butoften can be controlled with non-diseasespecific therapy including ACEI and ARB
7 Introduction In patients who develop recurrent and de novo disease , there is a 190% increased risk of losingthe graft compared with those without recurrentand de novo disease.Glomerulonephritis in the allograft is alsoassociated with a reduction in long-term (5-year)survival
9 Introduction Variables that have been found to be associated with recurrence included younger age, malegender, underlying GN as a cause of ESRD andretransplantsHigher prevalence in young ages is probablyexplained by the more frequent occurrence of GNin this group.
10 Introduction No penalty paid in terms of increased recurrence of GN for recipients who received theirtransplants for GN and were maintained onsteroids-free IS regimen.
12 Focal glomerular sclerosis FGS is the disease entity that carries thehighest incidence of clinically significantrecurrent disease with the greatest impact ongraft survival of any of the glomerular diseases
13 Focal glomerular sclerosis The overall recurrence rate in FGS is about 30%50% of these grafts are lost from recurrentdisease in 5 years .
14 Focal glomerular sclerosis The mean time to recurrence of FGS is short, 10-14 days, but recurrences have been reportedwithin hours and up to 6 months aftertransplantation.
15 Focal glomerular sclerosis Up to 50% of patients with recurrent FGS alsodevelop acute renal failure, 80% becomenephrotic, and hypertension and hematuria arecommon
16 Focal glomerular sclerosis Clearly, recurrence is more common in youngerpatients. Patients under 5 years of age have a 50%likelihood of recurrence versus only 10%-15% inpatients older than 30 years
17 Focal glomerular sclerosis Caucasian recipients seem more likely to haverecurrences than African-Americans. Rapidprogression of the underlying disease frominitial diagnosis to development of ESRD,particularly if it occurs within 3 years, alsopredicts recurrence.
18 Focal glomerular sclerosis Recurrence itself is a very bad prognostic signthat predicts recurrence in second allograft.Over 70% of such grafts have another recurrenceand most are lost. Thus, a history of graftloss from recurrent FGS virtually precludessubsequent successful transplantation in thatrecipient.
19 Focal glomerular sclerosis The pathogenesis of FGS is unclear, however acirculating permeability factor that is removed byplasmaphresis has been suspected to play a roleHowever recent data suggested the absence orloss of an inhibitor factor could be the cause
20 Focal glomerular sclerosis Further complicating the picture is therecognition of the pivotal role of podocytesproteins(podocin, nephrin, and actinin) in FSG
21 Focal glomerular sclerosis Early institution of plasmaphresis is important asthe effectiveness of treatment decreases withincreased number of sclerosed glomeruli.Relapses after cessation of plasmaphresis can beprevented by chronic phresis or concurrentcyclosporine or cyclophosphamide therapy
22 Focal glomerular sclerosis The role of preemptive perioperativeplasmaphresis in high risk groups still awaitsfurther studies.There is one recent case report of completeremission of FSG with rituximab
23 Focal glomerular sclerosis A number of case reports reported thedevelopment of de novo FSG when cyclosporinewas switched to sirolimus with subsequentimprovement after switching back to cyclo.Paradoxically sirolimus has achieved completeremission in 12 out of 21 steroid resistant FSG inanother study
24 Membranous Nephropathy Secondary causes of MN (infection,malignancy… etc) should be screenedIdiopathic MN recurs in 10-30%Recurrent disease should be differentiated fromde novo disease which is the most common denovo GN in renal allograft
25 Membranous Nephropathy The clinical presentation of recurrent MN ischaracterized by nephrotic range proteinuriawith a mean onset time of (10-24) months post-transplant as compared with the more insidiousand later onset of de novo MN (24-36) months
26 Membranous Nephropathy Recent studies showed antibodies against‘neutral endopeptidase’, a protein expressed onthe human podocyte cell membrane might beplaying a role in MGRisk factors for recurrence include male sex,rapid course of initial disease and LRD kidneysGraft failure from recurrence is 10-15%
27 Membranous Nephropathy Cyclosporine and MMF which have been used inthe treatment of primary MN do not prevent orchange the course of recurrent diseaseNo reports to suggest superiority of tacrolimus orcyclophosphamide over cyclosporine
28 MPGN Secondary causes of MPGN should be treated to reduce the risk of recurrence.Type I and II primary MPGN have high rate ofrecurrence after transplantation, 20-50% and 80-100 %respectively
29 MPGN Risk of recurrence increases in those with HLA- B8DR3, LRD and previous graft loss due toMPGNRecurrent disease is more common in type II andpresents with non-nephrotic range proteinureaComplement level has nothing to do with the riskof recurrence
30 MPGN Type II usually has more aggressive golmerular changes and a poorer prognosisNo effective therapy is available
31 Pauci-Immune Crescentic GN Pretransplantation course, cANCA, pANCA titer,disease subtype(WG, MPAN or CGN) in theabsence of clinically active disease, duration offollow up or donor type, do not predictrecurrence.Recurrence rate is around 20%
32 Pauci-Immune Crescentic GN It is advisable to defer transplant until the diseaseis inactivePatients with renal relapses showed goodresponse to cyclophopsphamide.
33 Pauci-Immune Crescentic GN For patients with cellular crescent and highANCA titer, favorable outcome has beenreported with combined cyclophosphamide,plasmaphresis with or without intravenousimmunoglobulin
34 SLE Histological recurrence has been reported in 30% Clinically significant recurrence occurs in 2-9%Most center postpone re-transplant until thedisease is quiescent for 6-9 months
35 SLE The duration of dialysis before transplantation and the serological markers in the absence ofclinically active disease do not predict recurrenceMMF has been shown to be very efficient.Graft loss due to recurrent lupus is uncommon,2-4%
36 SLE Long term patients and graft survival are similar to kidney allograft recipients with otherunderlying disease.
37 Anti-GBM Histological recurrence has been reported in 50% if transplantation is performed while circulatinganti-GBM antibodies are still presentDefer transplantation until the disease becomequiescent and the anti-GBM antibodies becomeundetectable for 12 months
38 Anti-GBM Good response has been reported in one patient with steroids, plasmaphresis andcyclophosphamide, another patient respondedwell to immune adsorption andcyclophosphamide
39 Immunoglobulin A Nephropathy IgAN is the commonest GN worldwide andaccounts for 20 % of renal failure of all renaltransplant cases.Great variation in the incidence of recurrence hasbeen reported by many centers as most centersperform biopsies only when patients aresymptomatic, underestimating the real number
40 Immunoglobulin A Nephropathy For centers where routine biopsies were beingcarried out, histological recurrence had beenreported in %Recurrence rate for patients with renal biopsiesdone for clinical symptoms ranges from 13-50%
41 Immunoglobulin A Nephropathy Recurrent disease is not as benign as had beenreported previouslyGraft loss from the severest form ranges from1.3 to 16 %No single parameter including age, gender, race,HLA or biochemical characteristic can predictrecurrence
42 Immunoglobulin A Nephropathy The relationship between recurrence and donortype remains controversial except in the familialform of IgAN where recurrence is high in LRDcasesRenal allograft survival in the first 10 years aftertransplantation is better when compared to otherprimary disease
43 Immunoglobulin A Nephropathy The situation is different for patients with priorgraft loss due to IgAN where the recurrence riskin the second transplant is %, and patientsshould be excluded from LRD listThere is no effective therapy to prevent recurrentIgAN
44 Immunoglobulin A Nephropathy Despite initial enthusiasm about MMF, recentdata are not substantiatedData on sirolimus is limitedSteroids-free or rapid steroid withdrawalregimen does not seem to affect recurrence risk
45 Immunoglobulin A Nephropathy ACE-I and ARB are used in proteinuric patients.HSP recurrence rate after transplantation issimilar to IgAN
46 Conclusion With improving long-term renal allograft survival, recurrent disease has increasedprominence as a significant contributorto late graft loss.Knowledge of the risk factors forrecurrence, onset time and impact on graftfunction is prerequisite to informed decisions
47 Conclusion Apart from plasmaphresis for patients with recurrent FSGS, there is no consensus onStrategies to prevent or treat recurrentglomerular disease in the kidney allograft.
48 Conclusion Also, in spite of the controversy over the risk of recurrence with certain types ofglomerulonephritis when the source of allograftis from living donors, the graft survival is largelycomparable to patients with other causes of end-stage renal failure. Thus, living related kidneyDonation can still be encouraged
49 Conclusion Caution should be exercised in patients with previous rapid graft loss due torecurrent disease in view of themarkedly increased risk with subsequenttransplants.