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 .
 focal segmental glomerulosclerosis ( fsgs ) causes glomerular lesions that can progress to end - stage renal disease . 
 it is suspected to be caused by a circulating factor that is amenable to plasmapheresis removal and exhibits a risk for recurrence in the renal allograft . 
 we present two patients with fsgs recurrence in their allograft kidneys diagnosed by biopsy after significant proteinuria developed in the posttransplant setting . 
 treatment with therapeutic plasma exchange induced long - term remission in both patients . 
 spot urine protein : creatinine ratios were monitored and treatment was continued until a target of < 0.5 was achieved . in patient number two , 
 a second peak in proteinuria and azotemia was ultimately attributable to ureteral stenosis and these values normalized following repair . in conclusion , 
 therapeutic plasma exchange is an effective treatment for fsgs recurring following renal transplant . 
Introduction
Case 1
Case 2
Discussion
Conclusion
Statement of Ethics
Disclosure Statement