Recurrence of focal segmental glomerulosclerosis in renal allograft: An in-depth review Primary FSGS in the native kidneys FSGS is a clinico-pathologic syndrome that was first described in 1957 by Arnold Rich (1). FSGS is characterized by NS and progressive loss of renal function. It is the most common histo- pathologic diagnosis associated with idiopathic steroid-resistant NS in children. Of all the children with FSGS-associated NS, 65% are steroid resistant. FSGS is classified by light microscopy into five different variants (Columbia classification, Table 1) (2). Each subclass has a distinct pathogenesis and clinical course (3). In 10 to 30% of patients, FSGS presents with progressive CKD without NS (4). The incidence of FSGS seems to be increasing over the past four decades, from 7–10% in 1960s to 20–60% in 1990s, of the biopsies done in children (5–7). Within 10 yr of initial presentation, 50–70% of patients with FSGS will progress to develop CKD stage 5 requiring renal replacement therapy (8–10). Review of NAPRTCS 2007 Annual Report reveals that 14.3% of patients on dialysis and 11.4% of patients with renal transplant have FSGS as their primary diagnosis. FSGS is either primary (idiopathic) or second- ary to other disease processes such as viral infections (e.g., HIV, Parvovirus 19), drug tox- icity (e.g., captopril, pamidronate, heroin, lith- ium), reduced renal mass (e.g., reflux nephropathy, sickle cell disease), or obesity (3, 11). Primary FSGS is more common in children. The pathogenesis of FSGS (Fig. 1) varies depending on whether it is sporadic or genetic (12–14). Derangement in the immune system is implicated in the sporadic or non-familial forms of FSGS. T-cell dysfunction and cytokines have been reported to play a major role. Abnormal- ities in circulating permeability factors that induce proteinuria, as well as inhibitors of these permeability factors have been implicated in the non-familial forms. The familial, genetic forms result from abnormalities in gene transcription controlling assembly of slit diaphragm, actin- based cytoskeleton, and adhesion complexes, all of which are essential for the podocyte function, in maintaining an effective filtration barrier. Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glom- erulosclerosis in renal allograft: An in-depth review. Pediatr Transplantation 2010: 14: 314–325. Ó 2010 John Wiley & Sons A/S. Abstract: Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant man- agement of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti-calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS. Modini Vinai 1,2 , Pamela Waber 1 and Mouin G. Seikaly 1,2 1 Department of Pediatrics, University of Texas Southwestern Medical Center, 2 Department of Pediatrics, ChildrenÕs Medical Center of Dallas, Dallas, TX, USA Key words: FSGS – transplant – kidney – recurrence – children Mouin G. Seikaly, MD, Professor of Pediatrics, UT Southwestern Medical Center at Dallas and Director, Pediatric Kidney Transplant, ChildrenÕs Medical Center of Dallas, 1935 Motor Street, Dallas, TX 75235, USA Tel.: 214 456 6005 Fax: 214 456 6456 E-mail: [email protected]Accepted for publication 14 September 2009 Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ACTN-4, alpha-actinin-4; ARB, angiotensin receptor blockers; ATG, anti-thymocyte globulin; CKD, chronic kidney disease; FSGS, focal segmental glomerulo- sclerosis; LDL, low density lipid; NAPRTCS, North American Pediatric Renal Trials and Cooperative Studies; NS, nephrotic syndrome; PP, plasmapheresis; USRDS, United States Renal Data System; WT1, Wilms tumor 1. Pediatr Transplantation 2010: 14: 314–325 Ó 2010 John Wiley & Sons A/S. Pediatric Transplantation DOI: 10.1111/j.1399-3046.2009.01261.x 314
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Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin
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Recurrence of focal segmentalglomerulosclerosis in renal allograft:An in-depth review
Primary FSGS in the native kidneys
FSGS is a clinico-pathologic syndrome that wasfirst described in 1957 by Arnold Rich (1). FSGSis characterized by NS and progressive loss ofrenal function. It is the most common histo-pathologic diagnosis associated with idiopathicsteroid-resistant NS in children. Of all thechildren with FSGS-associated NS, 65% aresteroid resistant. FSGS is classified by lightmicroscopy into five different variants (Columbiaclassification, Table 1) (2). Each subclass has adistinct pathogenesis and clinical course (3). In10 to 30% of patients, FSGS presents withprogressive CKD without NS (4). The incidenceof FSGS seems to be increasing over the pastfour decades, from 7–10% in 1960s to 20–60% in1990s, of the biopsies done in children (5–7).Within 10 yr of initial presentation, 50–70% of
patients with FSGS will progress to developCKD stage 5 requiring renal replacement therapy(8–10). Review of NAPRTCS 2007 AnnualReport reveals that 14.3% of patients on dialysisand 11.4% of patients with renal transplant haveFSGS as their primary diagnosis.FSGS is either primary (idiopathic) or second-
ary to other disease processes such as viralinfections (e.g., HIV, Parvovirus 19), drug tox-icity (e.g., captopril, pamidronate, heroin, lith-ium), reduced renal mass (e.g., refluxnephropathy, sickle cell disease), or obesity (3,11). Primary FSGS is more common in children.The pathogenesis of FSGS (Fig. 1) variesdepending on whether it is sporadic or genetic(12–14). Derangement in the immune system isimplicated in the sporadic or non-familial formsof FSGS. T-cell dysfunction and cytokines havebeen reported to play a major role. Abnormal-ities in circulating permeability factors thatinduce proteinuria, as well as inhibitors of thesepermeability factors have been implicated in thenon-familial forms. The familial, genetic formsresult from abnormalities in gene transcriptioncontrolling assembly of slit diaphragm, actin-based cytoskeleton, and adhesion complexes, allof which are essential for the podocyte function,in maintaining an effective filtration barrier.
Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glom-erulosclerosis in renal allograft: An in-depth review.PediatrTransplantation2010:14:314–325.�2010JohnWiley&SonsA/S.
Abstract: Focal segmental glomerulosclerosis is a major cause ofchronic kidney disease requiring transplantation in children. Recurrencerate in the renal allograft transplantation is as high as 50%. Recurrenceof FSGS is associated with renal dysfunction and early graft loss. Todate, there is no established therapy for recurrent FSGS after renaltransplant. We have reviewed the current English literature in order tosummarize current practices with emphasis on graft outcome. Weconclude that despite multiple approaches to the post transplant man-agement of recurrent FSGS, none have been shown to be consistentlybeneficial. Currently, pheresis combined with high dose anti-calcineurinwith or without rituximab seems to be the most promising. Furthercontrolled studies are needed to define the optimal therapeutic regimensto treat recurrent of FSGS.
Modini Vinai1,2, Pamela Waber1 andMouin G. Seikaly1,2
1Department of Pediatrics, University of TexasSouthwestern Medical Center, 2Department ofPediatrics, Children�s Medical Center of Dallas,Dallas, TX, USAKey words: FSGS – transplant – kidney – recurrence– children
Mouin G. Seikaly, MD, Professor of Pediatrics, UTSouthwestern Medical Center at Dallas and Director,Pediatric Kidney Transplant, Children�s MedicalCenter of Dallas, 1935 Motor Street, Dallas, TX75235, USATel.: 214 456 6005Fax: 214 456 6456E-mail: [email protected]
Some of the genes with reported mutations inpatients with FSGS include nephrin (NPHS1),podocin (NPHS2), ACTN-4, CD2-associatedprotein (CD2AP), WT1 transient receptor po-tential cation 6 (TRPC6), and phospholipase � C(PLCE1/NPHS3) (15). The incidence of familialFSGS varies significantly depending on theregion of the world from where these studieshave originated (16). Studies from North Amer-ica, with a significant proportion of African-American patients, show the frequency ofNPHS2 mutations to be small (16). This is incontradistinction to studies from Europe, SouthAfrica, and Southeast Asia where the frequency
of mutations in the NPHS2 gene is as high as50% (16).FSGS is the most common kidney disease
known to recur after a kidney transplant and iscomplicated by higher rates of acute tubularnecrosis with an incidence of 11.8% in livingdonor transplants and 27.9% in deceased donortransplants (17). Patients with recurrent FSGSalso have higher incidence of delayed graftfunction and five-yr graft loss rates as high as30% to 50% (17–19). Understanding clinical andpathological differences of various types of FSGSin native kidneys, as well as its pathogenesis willfurther elucidate its diagnosis and management,as it recurs in renal allograft. This review aims atdescribing the epidemiology, pathogenesis, natu-ral history, available therapies, and future direc-tions for management of FSGS in renaltransplant.
FSGS in the renal allograft
Recurrent FSGS post-renal transplant remainsan enigmatic clinico-pathologic disease because itwas first described by Hoyer et al. in 1972 (20,
Table 1. Columbia classification (2, 3)
Type I: Tip lesion variant Segmental sclerosis atthe origin of proximal tubule
21). The majority of FSGS in renal allograft ispresumed to be recurrence of primary disease,with a smaller proportion being de novo. Hari-haran et al. (22) found documented recurrence inat least 53% of their patients with allograftFSGS. Proteinuria is the first sign of recurrence,sometimes developing within a few hours post-renal transplant, with characteristic histo-patho-logic findings, often developing later (23). Efface-ment of foot processes on electron microscopy isthe initial finding on renal biopsy, appearingwithin a week of recurrence. Light microscopicfindings develop several weeks later (24). Recur-rence of FSGS can develop any time within thefirst two yr post-renal transplant. FSGS is onlysecond to chronic rejection as a cause of post-transplant proteinuria, especially later in thecourse of the renal transplant.
Risk factors for recurrence and graft loss
Multiple risk factors have been associated withrecurrence of FSGS in the allograft (Table 2).Children have a higher incidence of recurrentdisease. Younger patients between six and 15 yr ofage are particularly at riskwith a recurrence rate ofup to a 40% (25, 26). Sener et al. (25, 27) havenoticed a higher recurrence rate among women intheir single center review, although other studieshave not noticed this difference. Non-AfricanAmerican children are at significantly higher riskfor recurrence and graft loss (26, 28, 29). Anaggressive primary FSGS prior to transplant, witha time interval between onset and CKD 5 of<three yr, is associated with higher recurrence(25–27, 29, 30). Heavy proteinuria pretransplantand early recurrent heavy proteinuria post-trans-plant are associated with a higher incidence ofrecurrence aswell (25, 27). Patientswithmesangialhypercellularity as well as with fewer scleroticglomeruli on the original native kidney biopsy,especially in association with a rapid progressionto CKD 5 prior to transplant, have an increasedincidence of recurrence (29, 30).Whether native nephrectomy is associated with
an increased risk of recurrence is still uncertain.
Odorico et al. retrospectively evaluated the effectsof bilateral native nephrectomyprior to transplantin patients with CKD 5 because of primaryglomerulonephritis (25, 31). The incidence ofrecurrent FSGS was 40% in the nephrectomizedpatients as opposed to 16.1% among non-neph-rectomized patients. It is speculated that nativekidneys act to absorb permeability factors. Otherstudies among Japanese children, however, didnot support these findings (32). Patients withhistory of prior transplant loss secondary torecurrence have a very high risk of recurrence inthe current allograft, with rates as high as 80% inthe second transplant and >90% in the third andsubsequent transplants (26, 33).The type of induction therapy for post-trans-
plant immunosuppression is suggestive to have aneffect on recurrence of FSGS as well. Rafaat et al.(34)havenoticeda significantlyhigher incidenceofrecurrence with the use of anti-lymphocyte sera intheir single center experience. This effect wasmorepronounced with ATG, with seven of the eightpatients treated developing recurrence. Hubschet al. (35), in their single center experience atMiami, compared the incidenceof recurrencepriorto and after starting to use daclizumab for induc-tion. They found the odds ratio for developingrecurrence, with daclizumab use, to be 8.3. Cyclo-sporine use has been associated with lesser recur-rence especially in comparison with sirolimus (36,37). In fact, de novo FSGS has been reported withsirolimususe(36,38).Earlier studiessuggestedthatkidneytransplantsprocuredfromlivingdonorsareat a higher risk of disease recurrence and graftfailure. The more recent studies show graft loss inpatients with FSGS to be similar for living donorand deceased donor transplant (39, 40). But livingdonor transplants lose the graft survival advan-tage, seen in non-FSGS transplants, over thedeceased donor transplants (39).Finally, genetic forms of FSGS have a lower
incidence of recurrence (41). Twenty-five percentof patients with NPHS1 mutations develop denovo glomerulonephritis of the allograft, result-ing from podocyte injury caused by anti-nephrinantibodies (42). Although recurrence has beenreported in patients with homozygous and com-plex heterozygous NPHS2 mutations, the recur-rence rates are very low (3%) (43–47). On theother hand, simple heterozygous NPHS2 muta-tions have a similar incidence of recurrence as thenon-familial forms.
Diagnosis of recurrence in renal allograft
Recurrent FSGS disease can be symptomaticvery early in the post-transplant period. The first
Table 2. Causes for post-transplant proteinuria
Ischemia-reperfusion injury (ATN)Proteinuria from native kidneysRecurrence of FSGSAcute rejectionDrugsInfectionsNephron under dosingChronic allograft nephropathyOthers (hypertension, diabetes)
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sign of recurrence is often significant proteinuria(urinary protein (mg/dL) to creatinine (mg/dL)ratio >0.5) (48, 49). This can occur as early asthe first 48 to 72 h post-transplant. Progressivedecline in serum albumin develops within a fewdays and generalized edema ensues soon after.Early recurrence can lead to delayed graftfunction requiring dialysis (25). A renal biopsyis often needed for definitive diagnosis. Kidneybiopsies performed soon after recurrence, up tofour to six wk, mostly show minimal changes onlight microscopy and foot process effacement onelectron microscopy (30). Later in the course ofrecurrence, biopsies may show evidence of FSGSof the same histological subclass as in nativekidneys (fidelity), by light microscopy (50).Glomerular and tubular proteinuria not re-
lated to FSGS is not uncommon post-renaltransplant (Table 2). In patients whose primarydisease is FSGS, it is often difficult to distinguish,early in the course, between proteinuria second-ary to FSGS recurrence and that normally seenin the immediate post-transplant period. Thisearly proteinuria can result from various causesincluding proteinuria from the native kidneysand secondary to ischemia–reperfusion injury tothe graft. Hence, during this early post-trans-plant period, the diagnosis of FSGS recurrence,while suspected, is difficult to ascertain. Non-FSGS proteinuria (urinary protein/creatinineratio >0.2) decreases in the first three wk butcould persist up to nine wk post-transplant (48,51, 52). Some practices recommend nephrectomyto facilitate early diagnosis and intervention inrecurrent FSGS. In children with post-transplantproteinuria, there is no difference in either theduration or the rate of decline, of proteinuria,between nephrectomized and non-nephrectom-ized patients (48). Myslak et al. (52) reportedpersistent proteinuria >1.5 g/day and/or in-crease in proteinuria by >0.5 g/day beyondthree wk post-transplant and dropping serumalbumin to be highly suggestive of FSGS recur-rence. Clinical acumen is often needed for theearly diagnosis and management. Other testssuch as monitoring glomerular permeability fac-tor have not proven to be of clinical value (53,54). Because most FSGS recurrence occurs withthe first two yr after renal transplant, anyproteinuria that develops beyond this period isoften attributed to chronic allograft nephrop-athy.
Pathology of recurrent FSGS in renal allograft
The Columbia classification seems to have abearing on recurrent FSGS in the transplant
kidney. IJpelaar et al. (50) recently reviewedfidelity of type of FSGS recurrent in the trans-planted kidney to the type of FSGS in the nativekidney. They looked at 19 patients with recurrentFSGS and found 81% concurrence betweenprimary disease type and recurrent disease type.Based on these findings, they propose threedistinct patterns of recurrence: Type I withfidelity to native disease (60%), Type II withfidelity to native disease after a minimal changeintermediate (20%), and Type III with no fidelityto native disease (20%). These results support thehypotheses that the pathogenesis of FSGS in theallograft is multi-factorial and that primarydisease process continues post-renal transplant.
Pathogenesis of recurrent FSGS in renal allograft
Pathogenesis of recurrence depends on whetherprimary disease is hereditary or sporadic. FSGSdeveloping post-transplant in patients withNPHS1 mutation is because of pre-existinganti-nephrin antibodies in the recipients (42).The pathogenesis of recurrence of FSGS inpatients with homozygous NPHS2 was initiallyspeculated to be secondary to anti-podocinantibodies; however, no such antibodies havebeen demonstrated to date (55). Caridi et al. (46)proposed a possible link between heterozygousNPHS2 mutations in the donor kidney andpersistence of proteinuria with recurrence ofFSGS in the transplant recipient.The pathogenesis of recurrent FSGS in non-
genetic forms is probably multi-factorial. Shal-houb was the first to propose the presence of acirculating chemical mediator secreted by T cellsthat is toxic to the glomerular basement mem-brane, as a possible cause for nephrosis (56). Adecade later, Savin et al. developed an in vitroassay to quantify the activity of such a factortermed ‘‘permeability factor’’ in 1990s. Theirfurther work has characterized the factor as alow-molecular-weight protein with an anioniccharge and an affinity for protein A and galac-tose (57–59). Mechanisms by which the ‘‘perme-ability factor’’ causes nephrosis have been thesubject of extensive speculation. It may havedirect effects on the nephrin and podocin in thepodocyte, resulting in podocyte injury (60).Other mechanisms proposed include alteredphosphorylation of cellular proteins in the podo-cyte, alteration in the activity of serine proteases,and induction of integrin-like kinase activitythat leads to detachment of podocyte fromthe glomerular basement membrane (59, 61,62). This factor has also been shown toinhibit the synthesis of nitric oxide, probably by
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up-regulating asymmetric dimethylarginine, anendogenous inhibitor of all nitric oxide synthas-es. As a result, the anti-fibrotic effect in themesangium, of nitric oxide, is lost leading toprogressive glomerulosclerosis (63).Further work by various researchers has pro-
vided more insights into the circulating factortheory. Lack of correlation between the in vitroactivity of the permeability factor and clinicalstatus of the patients, as well as identification ofthe neutralizing effect of normal serum againstthe diseased serum has led to the ‘‘missing factor’’theory (53, 54). The urine of patients is found toneutralize the permeability factor activity of theserum, suggesting loss of an inhibitor in the urine(64). It has also been demonstrated that despitethe induction of remission with cyclosporine,patients continued to have permeability factoractivity (53). And permeability factor activity hasbeen demonstrated even in patients with homo-zygous NPHS2 mutations (43). All these findingssuggest the possibility of deficiency of an inhib-itor to the normally occurring permeability factoras a primary cause for proteinuria and podocyteinjury.
Management of recurrent FSGS
Although we have made some progress in theunderstanding of pathogenesis of recurrentFSGS, the morbidity and graft loss resultingfrom recurrence continue to be significant. Man-agement remains controversial, and our currentapproach is often based on anecdotal evidence,derived from non-blinded, non-randomized,small case series. Well-designed clinical trialscomparing various reported therapies and ther-apeutic regimens are lacking. Goals for manage-ment often include treatment aimed atminimizing the initial injury to the allograftoccurring from the circulating factors, followedby T cell and B cell suppression to preventimmunological injury and finally providing long-term nephro protection. The following discussionsummarizes current approaches to managementof recurrent FSGS.
PP and immunoadsorptive therapies
PP and Protein A column immunoadsorptivetherapy have been considered in the managementof recurrent FSGS because recognizing the roleof circulating factors in the pathogenesis. Arteroet al. (65) showed that the decrease in proteinuriaand induction of remission with the use of PP inpatients with recurrent disease were associatedwith decrease in the circulating permeabilityfactor. Dall�Amico et al. (27) used PP to induce
remission and followed it with a two-monthcourse of cyclophosphamide to sustain remission.Over the past two decades, multiple case series
using PP, with variable degrees of success, havebeen reported by various authors (Table 3) (18,19, 27, 30, 35, 43, 66–71). PP is most beneficialwhen used early in the course of recurrence,when, recurrence occurs early post-transplant(typically within a month) (30, 67, 70). Most caseseries have reported about 80% decrease inproteinuria following PP. Pediatric patients seemto have better outcomes in response to PP, withremission rates of 60 to 80% (18, 35, 68). Thenumber of treatment sessions needed to achieveremission is variable. Most patients seem to needbetween 8 and 12 treatments to achieve remis-sion. Typical PP prescription is 1–2 times plasmavolume exchanges and about 3–4 treatments perweek until remission is achieved, usually around10 sessions. Some reported protocols use aweaning protocol to sustain remission. A signif-icant proportion especially among adult patientsseem to require long-term PP (18). Belson et al.(72) have reported long-term use of PP incombination with protein A column adsorptionin a pediatric patient with maintenance of clinicalremission.Prophylactic PP prior to transplant has been
attempted in patients at high risk for recurrencewith variable outcome. Gohh et al. (73) looked atthe effect of prophylactic therapy in 10 patientsat high risk for recurrence. Five of these patientsreceived prophylaxis and the other five did not.The prophylaxis group had no recurrence whencompared to the no-prophylaxis group with a60% recurrence. Protocol used was a total ofeight single-volume treatments over a period oftwo wk. Living donor transplants received thefirst treatment one wk before the transplant, anddeceased donor transplants received the firsttreatment within 24 h of transplant. Otherauthors found no significant benefit from pro-phylactic PP (18, 35).Savin et al. have shown that the putative
circulating factor has an affinity for Protein Acolumn (59, 74). Dantal et al. used protein Acolumn adsorptive therapy in patients withrecurrent FSGS and showed that it decreasesproteinuria by about 82% at the end of the cycle(75, 76). But, because then, it has not been usedby itself. Its use is mostly reported in combina-tion with PP.
Cyclosporine A
Immunosuppressive effects of cyclosporine pri-marily result from inhibition of T helper cell
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activation and inhibition of release of cytokines.Sharmaet al. (77) havepostulated that someof theeffects of cyclosporine may be mediated throughincrease in glomerular cAMP. Even though theexact mechanism of action, in patients withsteroid-resistant NS, is still debated, use of cyclo-sporine in the management of FSGS, prior totransplant, is well accepted. Uncontrolled clinicaltrials evaluating the use of cyclosporine in patientswith recurrence in the transplant kidney have beeninconclusive (66, 78–80). Anecdotal reports ofhigh-dose therapy with a goal to maintain highserum levels suggest some beneficial effects (37,81). The rationale behind maintaining a highcyclosporine blood level is to overcome the effect
of high serum cholesterol often seen in patientswith recurrent FSGS after renal transplant.Cyclosporine is incorporated into the peripherallymphocytes through LDL receptors on the cellsurface. High blood levels of LDL increase theamount of cyclosporine bound to this lipo protein,which may in turn down-regulate the LDL recep-tors on the cell surface and subsequently reducethe cellular uptake of LDL–cyclosporine complex(82, 83). Thus, hypercholesterolemia can inhibitthe effect of cyclosporine in idiopathic NS. Themechanism by which high-dose cyclosporineinduces remission after FSGS, recurrence in renaltransplant is not known. A case series of 17childrenwith recurrence showed that 3 mg/kg/day
Table 3. Summary of studies evaluating PP as a therapy for recurrent FSGS
A, adult; C, child; N-patients, total number of patients in the study; N-Recur, number with FSGS recurrence; PP, number that received plasmapheresis; T-Recur, time torecurrence post-transplantation; d, day; w, week; m, month; y, year; PP protocol, plasmapheresis protocol used; D-PP, duration of plasmapheresis; Md, medianduration; R, range for duration; N-Rx, number of treatment sessions; ATG, anti-thymocyte globulin; FK, tacrolimus; Srl, sirolimus; MMF, mycophenolate; P, steroids;RTX, rituximab; IL2Rb, interleukin 2 receptor blocker; CsA, cyclosporine; AZ, azathioprine; OKT3, muromonab; Dxs, deoxysperagualin; MZ, mizoribine; ALG, anti-lymphocyte globulin; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CP, cyclophosphamide; Rm/T, patients achieving remission/total patients receiving plasmapheresis
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of IV cyclosporine therapy for three wk followedby an oral dose to maintain trough levels between200 and 300 ng/mL achieved remission in 14patients within 28 days (84). Rafaat et al. (85)have reported using high-dose oral cyclosporine,with good results. This beneficial effect seems to bespecific to cyclosporine among other calcineurininhibitors. Remission of FSGS has been reportedin patients, with recurrence while on tacrolimus,after switching to high-dose cyclosporine (86).
Cyclophosphamide
Cyclophosphamide reduces lymphocyte numbersand alters the balance of lymphocyte subsets. Theresulting immunosuppression presumably in-duces remission in primary FSGS. Reports ofcyclophosphamide use for induction of remissionin patients with recurrent FSGS are limited tosmall case series. Kershaw et al. (87) used an 8–12 wk course of high-dose cyclophosphamide (1–2 mg/kg/day) in three pediatric patients withpost-transplant recurrent FSGS and achievedsustained remission in two of them. The thirdpatient only achieved partial remission. Morerecently, cyclophosphamide use in combinationwith PP has shown promising outcome. Cochatet al. (88) showed sustained remission in threepatients with recurrent FSGS using a therapeuticprotocol consisting of PP, steroid pulse, andcyclophosphamide. Each of the patients under-went 10 sessions of PP in two wk followed by onesession per week for two months. They alsoreceived a steroid pulse (250 mg/m2/day) forthree days and cyclophosphamide (about 2 mg/kg/day) for two months. Dose of cyclophospha-mide was adjusted based on the white blood cellcount. Cheong et al. (30) were less successfulwith a similar regimen, achieving sustainedremission in only two of a total of six patientswith post-transplant recurrent FSGS. Dall�Ami-co et al. (27) used cyclophosphamide in combi-nation with PP, without steroid pulse, in 11pediatric patients and achieved sustained remis-sion in seven patients. Severe immunosuppres-sion, gonadal toxicity, and malignancies are thethree major long-term concerns that limit thecumulative dose of cyclophosphamide used in apatient. The current use of cyclophosphamide isinfrequent.
Rituximab
Rituximab is a genetically engineered, chimericmouse/human monoclonal antibody acting onCD-20 surface marker of B-lymphocytes andcausing selective depletion of B-lymphocytes(89). Its role in management of NS was identified
serendipitously while treating idiopathic throm-bocytopenic purpura in a patient with NS (90).Similarly, Nozu et al. (91) noted remission ofrecurrent FSGS in the transplanted kidney whiletreating post-transplant lympho-proliferative dis-order with rituximab in a 12-yr-old patient. Afew other case reports suggested similar successwith rituximab combined with PP (92–95). Hris-tea et al. (93) report sustained remission in a22-yr-old patient with recurrent FSGS in thetransplant kidney using rituximab in combina-tion with PP and low-dose oral cyclophospha-mide. Yabu et al. (96) reported the failure ofrituximab as a single agent to induce or sustainremission in four adult patients with recurrentFSGS in renal allograft. More recently, Hicksonet al. (18) reported the use of rituximab incombination with PP in four pediatric patientswith living related donor transplants, three ofthese patients received prophylactic PP startedpretransplant. All four of them showed sustainedremission, although three reached nadir urineprotein excretion only after several months aftertherapy. One of the patients was PP dependentprior to therapy with rituximab and was success-fully weaned off of PP after the therapy. Thetypical regimen used in all these reports is 2–6doses of 375 mg/m2/dose given once every one totwo wk. Younger patients seem to have morefavorable response to rituximab therapy (18).Also, resolution of proteinuria and remission ofNS may not be apparent for up to nine monthsafter therapy, necessitating extended follow-up todetermine responsiveness (18, 94).
Agents acting on renin–angiotensin system
Besides the immunologically mediated mecha-nisms, the renin–angiotensin system plays asignificant role in the glomerular injury occurringwith recurrent FSGS. Hoffman et al. (97) haveshown that angiotensin II causes protein leakageand podocyte damage, leading to the develop-ment of glomerulosclerosis in transgenic mice.Mizuiri et al. have shown increased angiotensinII receptors in the glomeruli of patients withrecurrent FSGS, suggesting a role for angiotensinin the pathogenesis (49). And finally, Hubschet al. (35) have shown that maximal benefit andsustained remission, in their patients with recur-rence, were obtained with PP in combinationwith ACEI and/or ARB and mycophenolate.Anti-proteinuric effect of ACEI and ARB inpatients with various nephropathies has beendemonstrated by White et al. (98), achieving48% and 31% reduction in proteinuria, respec-tively, with an eight-wk course. Despite all the
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above evidence, the role of ACEI and ARB in themanagement of early recurrent FSGS is not welldefined. Major concern is graft dysfunctionresulting from their early usage, post-transplant.
Management of thrombophilia
Vascular complications secondary to thrombosisare an important cause for early graft loss.Bresnahan et al. (99) reported graft thrombosisas the cause in 10% of children younger than fiveyr of age and in 5–6% of children>five yr of age,with graft loss post-cadaveric renal transplant.Technical problems associated with the surgicalprocedure contribute the most, to the risk ofthrombosis (100).Althoughhypercoagulable stateis less common as a cause, it is an importantmodifiable risk factor, especially in the presence ofheavy proteinuria associated with recurrence ofFSGS. Biesenbach et al. (101) reported an in-crease in monthly incidence of thrombovenous
and thromboemoblic complications from 1/18 to11/35 with occurrence of heavy proteinuria result-ing from recurrence of primary glomerulonephri-tis post-transplant. Hence, at-risk patients mustbe worked up for hypercoagulability. The work-up includes measuring protein C, protein S, andanti-thombin III levels and evaluating for presenceof lupus anti-coagulant, anti-phospholipid andanti-cardiolipin antibodies, and factor V Leidenmutations in the blood. In the presence of evidencefor thrombophilia, continuous intravenous hepa-rin infusion with a goal to maintain an activatedpartial thromboplastin time of 1.5 times baseline isrecommended for the immediate post-transplantperiod (102). Typically, intravenous heparin canbe switched to subcutaneous enoxaparin after 48 hpost-transplant. A 2.6-fold reduction in graft lossbecause of thrombosis has been reported with theuse of heparin in patients with hypercoagulablestates (103).Argatrobanhas beenused if heparin is
Fig. 2. Management algorithmof a child with recurrent FSGSpost renal transplantation.
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contra indicated because of the presence of hep-arin antibodies (102). Long-term anti-coagulationis needed for at least one yr post-transplantationand can be achieved with warfarin (104).
Other medications and regimens
Some centers have adapted intense immunosup-pressive regimens including different combina-tions of steroids, mycophenolate, azathioprine,cyclophosphamide, and cyclosporine. Thesestudies have not found any significant differencesin outcomes compared to the regimens using PPwith less aggressive immunosuppression. Torreset al. (105) have reported using meclofenamate, anon-steroidal anti-inflammatory agent, success-fully, to treat a 41-yr-old patient with recurrentFSGS in the second allograft. Patients withrecurrent FSGS, post-renal transplant, are proneto develop hypercholesterolemia, especially thosewho do not go into remission and those treatedwith steroids. Navaneethan et al. (106) haveshown significant decrease in all-cause mortalityas well as cardiovascular mortality in post-renaltransplant patients treated with statins. Statinsdecrease the cardiovascular risk and providenephroprotective effect independent of lipidmetabolism (106, 107).
Outcomes
The outcome of recurrence of FSGS in atransplant kidney is variable and dependent onmultiple factors. The spectrum of severity ofoutcome varies from immediate graft loss toslowly progressive proteinuria with chronic allo-graft dysfunction to complete remission with nolong-term consequences on the graft. Incidenceof graft loss in the first five yr post-transplant, inpatients with recurrent FSGS, is about 20–50%.Abbott et al. (108) retrospectively analyzed thedata from the USRDS registry for the periodOctober 1987–December 1996 to identify thefactors associated with graft loss resulting fromrecurrent FSGS. Recurrent FSGS accounted for18.7% of all graft losses in living donor recipientsand 7.8% in cadaveric renal recipients. Thehazard ratios (in parenthesis) were significantlyhigher for graft loss from recurrent FSGS inwhite recipients (2.38), white recipients receivingfrom African American donors (3.72), recipientsaged <7 (3.81), recipients aged between 7 and 19(3.01), and recipients with prior transplants(4.41). Although hazard ratio for recipients fromliving donors was 1.05, a trend toward loss ofliving donor advantage was noted. Early identi-fication of recurrence and management has asignificant bearing on the graft survival. Achieve-
ment of sustained remission has been shown toprotect against early graft loss and progression ofCKD in the transplant kidney.
Conclusions
Recurrence of FSGS remains a major clinicalissue is renal allograft. Despite multiple ap-proaches (Fig. 2) to the post-transplant manage-ment of recurrent FSGS, none have been shownto be consistently beneficial. Currently, PP com-bined with high-dose anti-calcineurin with orwithout rituximab seems to be the most prom-ising. Further controlled studies are needed todefine the optimal therapeutic regimens to treatrecurrent of FSGS.
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