focal segmental glomerulosclerosis ( fsgs ) is a clinicopathologic entity responsible for up to 20% of all cases of end - stage kidney disease in the united states . the incidence of fsgs is estimated at 7 per million individuals annually , has a slight male predominance ( male : female ratio 1.52 ) , and now represents the leading cause of idiopathic nephrotic syndrome in adults . although the pathogenesis of fsgs has not yet been fully described , the lesions that are induced include tuft collapse , segmental hyalinosis , and effacement of foot processes as revealed by electron microscopy . fsgs may also occur secondarily to certain genetic predispositions as well as disorders such as sickle cell disease , hiv nephropathy , and obesity ; in these instances , plasma exchange would not be considered a primary therapeutic option and treatment would instead be directed at the underlying driver . clinically , patients with fsgs manifest significant , nephrotic - range proteinuria , reduced renal function , and hypertension . eighty percent of fsgs cases are characterized as primary and are suspected to be caused by a circulating fsgs permeability factor , a low - molecular weight anionic protein . this same factor may be responsible for the recurrence of fsgs in the renal allograft , a scenario that occurs in approximately 2050% of primary allografts , most commonly within the first 3 months following transplant [ 4 , 5 ] . plasmapheresis removal of this factor appears to effectively treat many such cases [ 6 , 7 ] . recurrent fsgs can be suspected in patients who develop impaired graft function and significant proteinuria , defined as > 1 g/24 h in the posttransplant period . in many cases early recognition is therefore critical in properly diagnosing and managing this disorder . if recurrent fsgs is suspected ( even in the absence of a pretransplant history of fsgs ) then it is important to inform the pathology department of this suspicion so that biopsy specimens can be properly processed for electron microscopy , which is needed to evaluate for the foot process effacement characteristic of fsgs . the american society for apheresis guidelines designate recurrent fsgs in the renal allograft as a category i indication for therapeutic plasma exchange ( grade 1b , strong recommendation ) . we present two patients who developed recurrences of fsgs in their primary renal allografts treated with plasmapheresis and intravenous immune globulin ( ivig ) . a 39-year - old hispanic male with a history of end - stage renal disease ( esrd ) , hypertension and hypertrophic cardiomyopathy underwent deceased donor renal transplantation with thymoglobulin induction and standard steroid taper . he developed poor graft function and nephrotic - range proteinuria beginning on posttransplant day 1 . he required posttransplant hemodialysis on posttransplant days 3 , 6 , 8 , and 11 , as well as initiation of therapeutic plasma exchange and ivig on postoperative day 5 . renal transplant biopsies obtained on posttransplant day 7 confirmed the team 's suspicion for fsgs recurrence in the renal allograft . the patient is currently 4 years posttransplant and continues to demonstrate excellent renal allograft function ( serum creatinine of 1.6 ) with continued absence of proteinuria . a 37-year - old asian male with esrd due to primary fsgs underwent living unrelated renal transplantation performed with thymoglobulin induction followed by standard steroid taper . on posttransplant day 3 , significant proteinuria and a rise in serum creatinine developed . therapeutic plasma exchange was initiated on posttransplant day 4 and continued forward as noted in figure 3 . the patient also received a single dose of rituximab as well as ivig as treatment for his recurrent fsgs . a kidney biopsy on posttransplant day 8 was negative for rejection , but demonstrated typical foot process effacement changes consistent with fsgs recurrent in the renal allograft . following an initial complete response to therapeutic plasma exchange by posttransplant day 78 , a repeat allograft biopsy was obtained , which demonstrated improvement in the degree of foot process effacement and no evidence for rejection . the second bout of allograft dysfunction was ultimately discovered to be due to interval development of high - grade stenosis in the allograft ureter leading to a postobstructive nephropathy . as of posttransplant day 317 , blood urea nitrogen and creatinine ( both as mg / dl ) are 13 and 1.3 , respectively , and there is continued absence of proteinuria . we describe two cases of fsgs recurrent in the primary allografts successfully treated with therapeutic plasma exchange . in both cases , remission was associated with resolution of proteinuria and histologic improvement in the degree of foot process effacement on electron microscopy . , 10/11 patients resulted in a persistent reduction in 24-hour urine protein following 511 ( mean of 6 ) therapeutic plasma exchange procedures in conjunction with immunosuppressant medications . in another study , patients with recurrent fsgs not managed with plasma exchange were used as historic controls and were compared to 13 patients treated with plasma exchange . while persistent proteinuria contributed to graft loss in all untreated controls , 11/13 ( 85% ) patients treated with plasma exchange achieved either complete or partial remission . in another report , three of five patients with early recognition of recurrent fsgs treated with plasma exchange responded well , resulting in the reversal of foot process effacement and remission of proteinuria . among 14 pediatric patients with fsgs recurrent in the renal allograft , 9 were treated with 10 cycles of plasma exchange ( 3 cycles per week , the same regimen as ours ) with 5/9 ( 55.5% ) and 1/9 ( 12% ) achieving complete and partial remissions , respectively ; no remissions were observed among the 5 patients not treated with plasma exchange . in a treatment series of fsgs recurrent in the renal allograft , alachkar and colleagues   noted a complete response rate in 9/25 ( 36% ) and partial response in 10/25 ( 25% ) of patients treated with combinations of plasmapheresis and rituximab . interestingly , levels of soluble urokinase - type plasminogen activator ( supar )  a prospective permeability factor elevated in up to two thirds of those with primary fsgs  were found to correlate both with recurrence and response [ 11 , 12 ] . supar , however , is not specific for fsgs and has shown to be elevated in immune activation states , such as sepsis , hiv infection , and paroxysmal nocturnal hemoglobinuria , among others . furthermore , supar rebounds quickly following plasma exchange , and clinical response associated with plasma exchange treatment occurred despite sustained reductions in supar levels . .   showed no improvement in proteinuria upon addition of rituximab to chronic plasma exchange therapy in three retransplanted patients with recurrent fsgs . in contrast , kumar and colleagues , upon retrospective review , identified complete responses [ defined as reduction in urine protein : creatinine ( pr : cr ) ratio to < 0.2 ] and partial responses ( defined as decrease in urine pr : cr ratio by 50% and < 2.0 ) among 2/8 and 4/8 pediatric patients with recurrent fsgs . there have also been cases of responses to rituximab after incomplete or absent response to plasma exchange [ 18 , 19 , 20 ] . the precise mechanism of rituximab , a monoclonal antibody directed against cd20 , merits further research . a cd20-independent mechanism was studied by fornoni and colleagues , who described marked disruption of the actin cytoskeleton of podocytes exposed to fsgs sera . rituximab , through binding and preservation of sphingomyelin - related enzymes ( sphingomyelin phosphodiesterase acid like 3b - smpdl-3b ; acid sphingomyelinase ) , partially prevented the cytoskeletal damage incited by fsgs sera , thus protecting the podocyte filtration barrier and preserving function . this mechanism was corroborated by takahashi and colleagues , who demonstrated that rituximab , but not purified igg , significantly reduced proteinuria in an adriamycin - induced nephropathy rat model . this appears to be related to binding of rituximab to glomerular smpdl-3b and protection of podocyte - related proteins , nephrin and podocin . although precise mechanisms require further research to elucidate , the authors provide a theory that smpdl-3b is a key factor in the actin - cytoskeleton remodeling process within podocytes and that rituximab binding to smpdl-3b provides a salutary effect . evidence appears to support a similar protective action of cyclosporine a on podocytes , which blocks calcineurin - mediated desphosphorylation of synaptopodin , thus preserving cytoskeleton stability and preventing foot process effacement . there is also evidence of reduction in proteinuria with higher - dose intravenous ( but not standard - dose oral ) cyclosporine . inhibition of the renin - angiotensin system ( ras ) also has an antiproteinuric effect in recurrent fsgs patients . in one report , authors used triple ras suppression with angiotensin - converting enzyme inhibitor , angiotensin receptor blocker , and aliskiren , a direct renin inhibitor . their patient was treated with a combination of rituximab and plasma exchange , and the sequential triple ras inhibition by the latest addition of aliskiren led to a significant reduction in recalcitrant proteinuria . in a study by gohh et al . , preemptive plasma exchange treatment was explored as a means of reducing posttransplant fsgs recurrence in ten patients considered at high risk for recurrence ( esrd within 3 years of fsgs diagnosis or advanced azotemia at presentation or prior allograft loss due to recurrent fsgs ) . at a mean of 751  314 days three patients , each of whom had already manifested previous graft loss due to recurrent fsgs , developed biopsy - proven recurrence in the allograft . two of these patients returned to dialysis ; the third remained nephrotic with a creatinine of 2.6 mg / dl at the time of publication . park and colleagues , in an observational cohort study , found no difference in fsgs recurrence rates whether adult kidney transplant patients received pretransplant plasma exchange ( 1/4 , 25% ) , pretransplant plasma exchange plus rituximab ( 1/5 , 20% ) or no pretreatment ( 5/18 , 27.7% ) . in the pediatric population , gonzalez and colleagues   found absent protective effect of pretransplant plasma exchange with recurrence rates of 47 and 63% , respectively , for living and deceased donor first - time kidney transplantation . however , preemptive treatment did lead to a lower than expected rate of recurrence among patients undergoing transplant who had previously lost a graft due to recurrence . among those with recurrences , plasma exchange was highly effective as a treatment modality with 88% complete or partial remission rate . in patients referred for renal transplantation , a vague diagnosis of  hypertensive nephrosclerosis  particularly in younger patients  raises concern for the absence of a clearly defined etiology for primary renal failure . in some cases , a primary disorder such as fsgs may have been causative . this is of particular concern considering the high risk of recurrence of primary fsgs in the renal allograft . fsgs recurrent in the renal allograft can be diagnosed on electronic microscopy in proteinuric patients . the prompt institution of therapeutic plasma exchange is an important treatment modality , and rituximab may be added to this as adjunctive therapy . further research is required regarding the role of rituximab therapy either as a therapeutic modality in established fsgs recurrence or possibly as pretransplant prophylaxis to reduce the risk of recurrence . monitoring of treatment response to ongoing plasmapheresis treatment is accomplished through measurement of urine spot pr : cr ratios and serum creatinine . in responding patients , treatment should be continued until proteinuria has been reliably suppressed to below 0.5 g / day . was in part supported by grants from nih - ncrr ul1 tr000153 , kl2 tr000147 , and the juvenile diabetes research foundation international 17 - 2011 - 609 .