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Focal Segmental Glomerulosclerosis Recurrence in the Renal Allograft

2014; Elsevier BV; Volume: 21; Issue: 5 Linguagem: Inglês

10.1053/j.ackd.2014.06.004

1548-5609

Nicolae Leca,

Vasculitis and related conditions

Focal segmental glomerulosclerosis (FSGS) represents a common histologic pattern of glomerular injury associated with a multitude of disease mechanisms. The etiology of FSGS is often classified into primary (idiopathic) and secondary forms in response to genetic abnormalities, infections, toxins, and systemic disorders that lead to adaptive changes, glomerular hyperfiltration, and proteinuria. Our understanding of the pathogenic mechanisms responsible for FSGS was substantially enhanced in recent years because of major advances in the cell biology of the podocyte and parietal epithelial cell. Recurrence of FSGS occurs mainly in its primary form and is only rarely described in secondary forms. The re-enactment of pathologic mechanisms of FSGS as recurrent disease after kidney transplantation represents a biologic experiment that can provide unique insight. Nonetheless, recurrent FSGS remains a notable clinical problem that correlates with poorer renal allograft outcomes. This is the focus of this particular review, concentrating on the most recent developments. Focal segmental glomerulosclerosis (FSGS) represents a common histologic pattern of glomerular injury associated with a multitude of disease mechanisms. The etiology of FSGS is often classified into primary (idiopathic) and secondary forms in response to genetic abnormalities, infections, toxins, and systemic disorders that lead to adaptive changes, glomerular hyperfiltration, and proteinuria. Our understanding of the pathogenic mechanisms responsible for FSGS was substantially enhanced in recent years because of major advances in the cell biology of the podocyte and parietal epithelial cell. Recurrence of FSGS occurs mainly in its primary form and is only rarely described in secondary forms. The re-enactment of pathologic mechanisms of FSGS as recurrent disease after kidney transplantation represents a biologic experiment that can provide unique insight. Nonetheless, recurrent FSGS remains a notable clinical problem that correlates with poorer renal allograft outcomes. This is the focus of this particular review, concentrating on the most recent developments. Clinical Summary•Contemporary review of factors associated with FSGS recurrence in the allograft and their prognostic implications.•Updated review of pathogenic mechanisms leading to FSGS recurrence. •Contemporary review of factors associated with FSGS recurrence in the allograft and their prognostic implications.•Updated review of pathogenic mechanisms leading to FSGS recurrence. FSGS represents the most common primary glomerular disease that leads to ESRD in the United States. The incidence of FSGS has been increasing in the span of the last 30 years and accounts for 2.3% of incident cases of ESRD in the United States.1Kitiyakara C. Eggers P. Kopp J.B. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States.Am J Kidney Dis. 2004; 44: 815-825Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar The increase in the frequency of FSGS diagnosis is possibly a reflection of disease classification in relation to improvements in the understanding of the disease, podocyte biology, and overall more attention to diagnostic practices. The prevalence of FSGS as a cause of ESRD in kidney transplant recipients was estimated at 5% in a single-center study; however, with the addition of more detailed etiologic information, only 1.9% of cases appeared to fit stricter criteria of primary FSGS.2Hickson L.J. Gera M. Amer H. et al.Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence.Transplantation. 2009; 87: 1232-1239Crossref PubMed Scopus (135) Google Scholar The prevalence of primary FSGS in the pediatric kidney transplant recipients is larger at 8% to 11%.2Hickson L.J. Gera M. Amer H. et al.Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence.Transplantation. 2009; 87: 1232-1239Crossref PubMed Scopus (135) Google Scholar, 3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar Heterogeneity of etiologic mechanisms and the possibility of misclassification make difficult the ascertainment of the true incidence of recurrent FSGS after kidney transplantation. Most studies estimate the overall risk of recurrence in the range of 30% to 50%,2Hickson L.J. Gera M. Amer H. et al.Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence.Transplantation. 2009; 87: 1232-1239Crossref PubMed Scopus (135) Google Scholar, 3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar, 4Pardon A. Audard V. Caillard S. et al.Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients.Nephrol Dial Transplant. 2006; 21: 1053-1059Crossref PubMed Scopus (79) Google Scholar, 5Ponticelli C. Glassock R.J. Posttransplant recurrence of primary glomerulonephritis.Clin J Am Soc Nephrol. 2010; 5: 2363-2372Crossref PubMed Scopus (172) Google Scholar the higher values seen in the pediatric population.3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar For patients who have experienced allograft failure because of recurrent FSGS, the risk of recurrence in subsequent kidney transplants approaches 100%.5Ponticelli C. Glassock R.J. Posttransplant recurrence of primary glomerulonephritis.Clin J Am Soc Nephrol. 2010; 5: 2363-2372Crossref PubMed Scopus (172) Google Scholar Additional factors found to be associated with an increased risk of recurrence are younger age (particularly children aged 6-15 years), nonblack race, rapid progression of disease in the native kidneys (within 3 years from diagnosis), requirement for bilateral nephrectomy, and severity of proteinuria.6Shimizu A. Higo S. Fujita E. Mii A. Kaneko T. Focal segmental glomerulosclerosis after renal transplantation.Clin Transplant. 2011; 25: 6-14Crossref PubMed Scopus (33) Google Scholar, 7Sener A. Bella A.J. Nguan C. Luke P.P. House A.A. Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function.Clin Transplant. 2009; 23: 96-100Crossref PubMed Scopus (44) Google Scholar Living-donor transplantation, particularly living related, represents an additional risk factor in the pediatric population.8Baum M.A. Outcomes after renal transplantation for FSGS in children.Pediatr Transplant. 2004; 8: 329-333Crossref PubMed Scopus (75) Google Scholar Among histologic findings of FSGS seen in the native kidney biopsies at diagnosis, mesangial hypercellularity has been correlated with an increased risk of recurrence, likely a reflection of a more severe form of disease and steroid resistance.9Couser W. Recurrent glomerulonephritis in the renal allograft: an update of selected areas.Exp Clin Transplant. 2005; 3: 283-288PubMed Google Scholar Earlier reports estimated the risk of recurrence approaching 80% in those with mesangial hypercellularity and only 25% in those with minimal change disease seen on their initial biopsies.10Weber S. Tönshoff B. Recurrence of focal-segmental glomerulosclerosis in children after renal transplantation: clinical and genetic aspects.Transplantation. 2005; 80: S128-134Crossref PubMed Scopus (81) Google Scholar The histologic classification of FSGS, which recognizes 5 histologic patterns of glomerular injury, seems to provide inconsistent correlation with the risk of recurrence after transplantation. Notably, recurrent FSGS with a different histologic classification from the native disease is well described, although 1 study found that 81% of recurrent lesions resembled the original histologic classification.11IJpelaar D.H. Farris A.B. Goemaere N. et al.Fidelity and evolution of recurrent FSGS in renal allografts.J Am Soc Nephrol. 2008; 19: 2219-2224Crossref PubMed Scopus (53) Google Scholar, 12Canaud G. Dion D. Zuber J. et al.Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS).Nephrol Dial Transplant. 2010; 25: 1321-1328Crossref PubMed Scopus (73) Google Scholar Among histologic subtypes, collapsing FSGS was less likely than other noncollapsing types to represent a recurrent disease process in a cohort of transplant recipients with an evidence of FSGS lesions on their kidney biopsies.13Swaminathan S. Lager D.J. Qian X. Stegall M.D. Larson T.S. Griffin M.D. Collapsing and non-collapsing focal segmental glomerulosclerosis in kidney transplants.Nephrol Dial Transplant. 2006; 21 (2607-2314)Crossref PubMed Scopus (49) Google Scholar Although the pathogenic mechanisms leading to secondary FSGS may still be present in the allograft recipient, in general, the secondary forms of FSGS are not thought to recur after renal transplantation. Furthermore, de novo FSGS-type lesions can be commonly seen in renal allografts that are sometimes difficult to discern from a recurrent form, particularly for those with subacute clinical presentations.6Shimizu A. Higo S. Fujita E. Mii A. Kaneko T. Focal segmental glomerulosclerosis after renal transplantation.Clin Transplant. 2011; 25: 6-14Crossref PubMed Scopus (33) Google Scholar, 14D'Agati V.D. Kaskel F.J. Falk R.J. Focal segmental glomerulosclerosis.N Engl J Med. 2011; 365: 2398Crossref PubMed Scopus (556) Google Scholar Additionally, multiple pathogenic factors causative of secondary FSGS can be encountered in the allograft, including adaptive pathogenic mechanisms (decreased nephron mass, urinary reflux, obesity), hypertension, infections (parvovirus B19), drug toxicity (m-TOR inhibitors), and diabetes. The observation that FSGS recurrence may occur immediately after transplantation strongly suggests the presence of a circulating factor in the recipient. As such, Chang and colleagues15Chang J.W. Pardo V. Sageshima J. et al.Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis.Transplantation. 2012; 93: 1238-1244Crossref PubMed Scopus (2) Google Scholar found a significant degree of podocyte foot process effacement in postperfusion allograft biopsies in 5 of the 7 patients in their cohort who experienced recurrent FSGS within the first month after transplantation (mean 4 days) compared with only 1 of the 12 patients without recurrence. Soluble urokinase-type plasminogen activator receptor (suPAR) has been recently proposed as a candidate for the elusive circulating factor causative of glomerular protein permeability since the initial reports of this concept by Savin and colleagues.16Savin V.J. Sharma R. Sharma M. et al.Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.N Engl J Med. 1996; 334: 878-883Crossref PubMed Scopus (626) Google Scholar Wei and colleagues17Wei C. El Hindi S. Li J. et al.Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis.Nat Med. 2011; 17: 952-960Crossref PubMed Scopus (649) Google Scholar found elevated levels of suPAR in two-thirds of their cohort of patients with idiopathic FSGS. SuPAR levels were particularly elevated in patients who experienced recurrence of FSGS after transplantation. Additionally, a retrospective study of 25 patients with recurrent FSGS found a significant correlation between the suPAR levels and the degree of podocyte effacement seen on electron microscopy. Furthermore, suPAR levels appeared to decline after treatment with plasmapheresis and rituximab.18Alachkar N. Wei C. Arend L.J. et al.Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy.Transplantation. 2013; 96: 649-656Crossref PubMed Scopus (54) Google Scholar The use of suPAR as a biomarker for disease recurrence has been evaluated in a recent study that looked at a cohort of 86 renal transplant candidates and 10 healthy controls. Serum suPAR levels were elevated in transplant candidates with advanced renal disease compared with healthy controls. However, suPAR levels could not discern the etiologies of kidney disease. Urinary suPAR levels were elevated in those patients who experience FSGS recurrence (n = 13) vs other ESRD diagnoses.19Franco Palacios C.R. Lieske J.C. Wadei H.M. et al.Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates.Transplantation. 2013; 96: 394-399Crossref PubMed Scopus (79) Google Scholar In a single-center, cross-sectional analysis, of 99 children, suPAR levels could not differentiate between FSGS, non-FSGS glomerular kidney disease, and healthy volunteers.20Bock M.E. Price H.E. Gallon L. Langman C.B. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: a single-center report.Clin J Am Soc Nephrol. 2013; 8: 1304-1311Crossref PubMed Scopus (77) Google Scholar The suPAR levels were also similar in the 34 renal transplant recipients with FSGS or non-FSGS diagnoses. In an accompanying commentary, Sever and colleagues21Sever S. Trachtman H. Wei C. Reiser J. Is there clinical value in measuring suPAR levels in FSGS?.Clin J Am Soc Nephrol. 2013; 8: 1273-1275Crossref PubMed Scopus (16) Google Scholar propose hypotheses that may explain variability in the suPAR results. These include specimen timing, handling and storage, plasma vs serum testing, and the associated level of inflammation. Jefferson and Shankland caution about a possible similarity between suPAR and early parathyroid hormone assays in relation to detection methodology. SuPAR circulates as fragments different in glycosylation and molecular sizes, which may translate in differences in biologic activity and reactivity with the currently commercial enzyme-linked immunosorbent assays potentially explaining some of the variability in the results reported to date.22Jefferson J.A. Shankland S.J. Has the circulating permeability factor in primary FSGS been found?.Kidney Int. 2013; 84: 235-238Crossref PubMed Scopus (18) Google Scholar Although suPAR remains a candidate, multiple other circulating factors, including cardiotrophin-like cytokine-1, vasodilator-stimulated phosphoprotein, and apolipoprotein A-I, have been evaluated for their contribution to the etiology of FSGS. Ongoing work is being done to clarify potential pathogenic mechanisms and to describe the clinical implications of these factors.23McCarthy E.T. Sharma M. Savin V.J. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2010; 5: 2115-2121Crossref PubMed Scopus (241) Google Scholar A recent case report documents the occurrence of de novo collapsing FSGS 1 month after transplantation in context of detectable antibodies against angiotensin II type I receptor.24Alachkar N. Gupta G. Montgomery R.A. Angiotensin antibodies and focal segmental glomerulosclerosis.N Engl J Med. 2013; 368: 971-973Crossref PubMed Scopus (41) Google Scholar It is unclear from the report if these antibodies were preformed or developed de novo after transplantation, and it remains to be seen if an antibody-mediated injury to the podocyte can represent a mechanism of recurrence in FSGS. Advances in proteomic analysis methods may provide additional biomarkers of interest in the future. As a recent example, the proteomic analysis in the urine and plasma of a cohort of transplant patients with idiopathic FSGS from Spain identified a strong association between recurrence of FSGS and a high-molecular weight form of apolipoprotein A-I, named ApoA-Ib, which was present in 13 of the 14 patients experiencing recurrent FSGS and in only 1 of the 61 patients without recurrence.25Lopez-Hellin J. Cantarell C. Jimeno L. et al.A form of apolipoprotein a-I is found specifically in relapses of focal segmental glomerulosclerosis following transplantation.Am J Transplant. 2013; 13: 493-500Crossref PubMed Scopus (41) Google Scholar The search for biomarkers useful in quantifying the risk of recurrence is ongoing and has overlapped the search for the circulating factors accounting for FSGS pathogenesis. To date, this distinction remains unclear as pretransplant interventions aimed at removal of circulating factors with plasmapheresis have not lead to convincing results in relation to decreasing the risk of FSGS recurrence.2Hickson L.J. Gera M. Amer H. et al.Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence.Transplantation. 2009; 87: 1232-1239Crossref PubMed Scopus (135) Google Scholar Mutations in multiple genes have been associated with FSGS, predominantly because of resultant phenotypic changes in podocyte structure and function. In general, genetic mutations are not considered among the pathogenic mechanisms that lead to disease recurrence. One notable exception is the mutation of NPSH2 gene, which encodes podocin. In a cohort of 13 subjects with mutations of NPSH2 gene, 5 (39%) were found to have clinically recurrent FSGS, more frequently observed in those with heterozygous mutations (3 of 4).26Bertelli R. Ginevri F. Caridi G. et al.Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin.Am J Kidney Dis. 2003; 41: 1314-1321Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The reported high recurrence rate was not reproduced in a subsequent analysis, and no clear mechanism is accountable for the recurrent process, particularly as the presence of antipodocin antibodies did not seem to play a role.27Becker-Cohen R. Bruschi M. Rinat C. et al.Recurrent nephrotic syndrome in homozygous truncating NPHS2 mutation is not due to anti-podocin antibodies.Am J Transplant. 2007; 7: 256-260Crossref PubMed Scopus (32) Google Scholar, 28Jungraithmayr T.C. Hofer K. Cochat P. et al.Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation.J Am Soc Nephrol. 2011; 22: 579-585Crossref PubMed Scopus (79) Google Scholar To date, 126 NPSH2 mutations have been identified in association with steroid-resistant nephrotic syndrome. These mutations carry an overall very low risk of recurrence after kidney transplantation.29Bouchireb K. Boyer O. Gribouval O. et al.NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum.Hum Mutat. 2014; 35: 178-186Crossref PubMed Scopus (60) Google Scholar Only 1 of 32 patients with homozygous or compound heterozygous NPSH2 mutations experienced recurrence of proteinuria after transplantation compared with 25 of 74 patients without NPSH2 mutations.30Weber S. Gribouval O. Esquivel E.L. et al.NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.Kidney Int. 2004; 66: 571-579Crossref PubMed Scopus (305) Google Scholar It remains unclear if in the presence of heterozygous mutations the risk of recurrent FSGS is even related to the NPSH2 mutations. In the African-American population, the higher prevalence of FSGS has been linked through genetic epidemiologic studies with polymorphisms of MYH9 and APOL1 genes. These findings are not associated with recurrent FSGS in the allograft and serve more as an example of potential reasons for increase in FSGS incidence through better disease classification.31Kopp J.B. Smith M.W. Nelson G.W. et al.MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.Nat Genet. 2008; 40: 1175-1184Crossref PubMed Scopus (588) Google Scholar, 32Pollak M.R. Kidney disease and African ancestry.Nat Genet. 2008; 40: 1145-1146Crossref PubMed Scopus (7) Google Scholar, 33Friedman D.J. Kozlitina J. Genovese G. Jog P. Pollak M.R. Population-based risk assessment of APOL1 on renal disease.J Am Soc Nephrol. 2011; 22: 2098-2105Crossref PubMed Scopus (38) Google Scholar Recurrent diseases after kidney transplantation represent exclusive in vivo experiments that help further define our understanding of the pathogenesis and disease progression. As such, the utmost importance of the podocyte, among the glomerular filtration barrier components, is demonstrated in the early recurrent FSGS. Massive levels of proteinuria can be seen within hours and days after transplantation despite minimal histologic changes confined only ultrastructurally to the podocytes. The rapid recurrence of FSGS after kidney transplantation also strongly suggests that a circulating, pathogenic factor is responsible for the disease, and newer findings suggest that suPAR may be responsible in a subset of patients. Conversely, when kidneys obtained from donors with FSGS or minimal change disease are transplanted, proteinuria subsides promptly in the allograft recipient.34Ali A.A. Wilson E. Moorhead J.F. et al.Minimal-change glomerular nephritis. Normal kidneys in an abnormal environment?.Transplantation. 1994; 58: 849-852Crossref PubMed Scopus (57) Google Scholar, 35Gallon L. Leventhal J. Skaro A. Kanwar Y. Alvarado A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation.N Engl J Med. 2012; 366: 1648-1649Crossref PubMed Scopus (25) Google Scholar Histologically, early FSGS recurrence is indistinguishable from minimal change disease appearance and ultrastructural wide spread podocyte foot process effacement.9Couser W. Recurrent glomerulonephritis in the renal allograft: an update of selected areas.Exp Clin Transplant. 2005; 3: 283-288PubMed Google Scholar As the disease progresses, the loss of podocytes through detachment or cell death is responsible for the development of glomerulosclerotic lesions.6Shimizu A. Higo S. Fujita E. Mii A. Kaneko T. Focal segmental glomerulosclerosis after renal transplantation.Clin Transplant. 2011; 25: 6-14Crossref PubMed Scopus (33) Google Scholar, 14D'Agati V.D. Kaskel F.J. Falk R.J. Focal segmental glomerulosclerosis.N Engl J Med. 2011; 365: 2398Crossref PubMed Scopus (556) Google Scholar Wei and colleagues36Wei C. Möller C.C. Altintas M.M. et al.Modification of kidney barrier function by the urokinase receptor.Nat Med. 2008; 14: 55-63Crossref PubMed Scopus (432) Google Scholar have shown that the membrane-bound urokinase-type plasminogen activator receptor activates β3 integrin that is responsible for the podocyte foot effacement and development of proteinuria. In a remarkable case, an allograft that was injured by a severe FSGS recurrence was explanted and retransplanted into a different recipient where it lead to marked improvement in proteinuria and renal function, strongly suggesting that reparatory mechanisms are possible.35Gallon L. Leventhal J. Skaro A. Kanwar Y. Alvarado A. Resolution of recurrent focal segmental glomerulosclerosis after retransplantation.N Engl J Med. 2012; 366: 1648-1649Crossref PubMed Scopus (25) Google Scholar Although podocyte loss was not specifically demonstrated in this case, any repair mechanism that leads to restoration of podocyte numbers is likely dependent on replacement by other progenitor-type cells because of the terminally differentiated nature of the podocyte. Activated parietal epithelial cells and cells of renin lineage have been proposed as cells that may evolve and replace injured podocytes.37Kowalewska J. Pathology of recurrent diseases in kidney allografts: membranous nephropathy and focal segmental glomerulosclerosis.Curr Opin Organ Transplant. 2013; 18: 313-318Crossref PubMed Scopus (10) Google Scholar, 38Pippin J.W. Sparks M.A. Glenn S.T. et al.Cells of renin lineage are progenitors of podocytes and parietal epithelial cells in experimental glomerular disease.Am J Pathol. 2013; 183: 542-557Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Notably, staining for CD44 (a marker of activated parietal epithelial cells) has been identified in podocytes at early stages of FSGS recurrence and has been proposed as another histologic finding associated with FSGS recurrence.39Fatima H. Moeller M.J. Smeets B. et al.Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant.Clin J Am Soc Nephrol. 2012; 7: 1852-1858Crossref PubMed Scopus (91) Google Scholar CD44 staining may also help differentiate recurrent FSGS from minimal change disease as 29% of the glomeruli from recurrent FSGS cases exhibited positive CD44 staining compared with only 2.6% of the minimal change disease cases and none of the controls. Two types of clinical manifestations are usually seen in the presence of recurrent FSGS. An early course of disease is manifested by an aggressive course with high-level proteinuria, usually detected within 48 to 72 hours after transplantation and associated with different degrees of renal dysfunction ranging from progressive impairment to dense acute kidney injury and requirement for dialysis.8Baum M.A. Outcomes after renal transplantation for FSGS in children.Pediatr Transplant. 2004; 8: 329-333Crossref PubMed Scopus (75) Google Scholar Other manifestations of the nephrotic syndrome promptly develop with progressive edema and declining albumin levels. Changes in blood pressure values are confounded by the degree of renal dysfunction and the increased incidence of delayed graft function seen with FSGS recurrence. Early post-transplant proteinuria is not uncommon after kidney transplantation. This finding may be related to ischemia-reperfusion injury of the allograft or originate from the native kidneys; nevertheless, it is quite uncommon for the severity of proteinuria to be in the nephrotic range. Non-FSGS recurrent proteinuria is usually self-resolving in the first few weeks after transplantation, but a heightened clinical attention and consideration for performance of a biopsy are required if recurrent FSGS diagnosis is entertained. In general proteinuria precedes the histologic findings of FSGS seen by light microscopy; however, the ultrastructural findings of podocyte effacement can be seen very early.15Chang J.W. Pardo V. Sageshima J. et al.Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis.Transplantation. 2012; 93: 1238-1244Crossref PubMed Scopus (2) Google Scholar A subacute course of FSGS recurrence has been described as well, where proteinuria and graft dysfunction develop slowly and progress over months and years. In the later post-transplantation period, multiple factors can contribute to the development of FSGS. As such, classification between recurrent and de novo FSGS can be blurred especially when significant chronic changes are found on biopsies. The general perception is that the degree of podocyte effacement is more pronounced in the primary vs secondary forms. The clinical utility of biomarkers like suPAR is yet to be demonstrated in relation to the clinical manifestations of recurrent FSGS. The lack of a broadly accepted guideline for the treatment of recurrent FSGS is associated with significant inconsistency in relation to therapeutic approach and represents a measure of the lack of efficacy of the currently available therapeutic options. Cravedi and colleagues40Cravedi P. Kopp J.B. Remuzzi G. Recent progress in the pathophysiology and treatment of FSGS recurrence.Am J Transplant. 2013; 13: 266-274Crossref PubMed Scopus (91) Google Scholar and Vinai and others3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar have recently reviewed in depth the treatment options available for treatment of recurrent FSGS. Overall, the studies available are unfortunately very small, mostly retrospective, and many are biased by multiple factors making their results very difficult to generalize. In general, inhibitors of the renin-angiotensin system are accepted for use in proteinuric renal diseases; however, their particular role in the treatment of recurrent FSGS is likely only additive to immunosuppressive interventions, and their use is limited by the potential for side effects in the early post-transplant period. Antilipemic and antithrombophilic approaches may be considered in the presence of severe nephrotic syndrome. Because of the significant likelihood of recurrence, pre-emptive approaches employed before transplantation have been proposed but are mostly unsubstantiated.3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar In general, plasmapheresis-based approaches are used for the early aggressive recurrence and have been correlated with success in obtaining partial or complete remission in two-thirds of the cases as concluded by Ponticelli and Glassock.5Ponticelli C. Glassock R.J. Posttransplant recurrence of primary glomerulonephritis.Clin J Am Soc Nephrol. 2010; 5: 2363-2372Crossref PubMed Scopus (172) Google Scholar The elements of the plasmapheresis prescription and treatment course are quite variable in the literature. At least 8 to 12 plasmapheresis treatments have been required for induction or remission, although dependence on long-term plasmapheresis dependence has been reported.3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar On a smaller scale, immunoadsorbption with protein A columns has been used with similar success independently or as addition to plasmapheresis; however, this treatment is not widely available3Vinai M. Waber P. Seikaly M.G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.Pediatr Transplant. 2010; 14: 314-325Crossref PubMed Scopus (90) Google Scholar; suPAR does not significantly bind to protein A columns for immunoadsorbption in vitro or in vivo.41Beaudreuil S. Zhang X. Kriaa F. et al.Protein A immunoadsorption cannot significantly remove the soluble receptor of urokinase from sera of patients with recurrent focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2014; 29: 458-463Crossref PubMed Scopus (14) Google Scholar Although the use of cyclosporine in the treatment of FSGS in the native kidneys is well accepted, its role in the recurrent disease in the allograft is questionable. Higher doses of cyclosporine may be effective and a podocyte-specific mechanism of action has been attributed to the inhibition of calcineurin-mediated dephosphorylation of synaptopodin.40Cravedi P. Kopp J.B. Remuzzi G. Recent progress in the pathophysiology and treatment of FSGS recurrence.Am J Transplant. 2013; 13: 266-274Crossref PubMed Scopus (91) Google Scholar The lymphosuppressive effect of cyclophosphamide motivated its use in a very small case series with varied success and with concerns of long-term toxicity. The use of rituximab has gained popularity in recent reports,40Cravedi P. Kopp J.B. Remuzzi G. Recent progress in the pathophysiology and treatment of FSGS recurrence.Am J Transplant. 2013; 13: 266-274Crossref PubMed Scopus (91) Google Scholar and it is possible that its effect is mediated by off-target binding SMPDL-3b on podocytes and effect on acid sphingomyelinase activity.42Fornoni A. Sageshima J. Wei C. et al.Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.Sci Transl Med. 2011; 3: 85ra46Crossref PubMed Scopus (402) Google Scholar Araya and colleagues43Araya C.E. Dharnidharka V.R. The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review.J Transplant. 2011; 2011: 374213Crossref PubMed Google Scholar observed some clinical response in 25 of 39 patients treated with rituximab, 17 (44%) of those experiencing complete remission of proteinuria. Additional reports of combination treatment with rituximab and plasmapheresis can be found in the literature with a similar success reported.44Tsagalis G. Psimenou E. Nakopoulou L. Laggouranis A. Combination treatment with plasmapheresis and rituximab for recurrent focal segmental glomerulosclerosis after renal transplantation.Artif Organs. 2011; 35: 420-425Crossref PubMed Scopus (39) Google Scholar Tumor necrosis factor alfa is thought to participate in pathogenesis of FSGS, and its blockade has been considered as a treatment strategy.45Leroy S. Guigonis V. Bruckner D. et al.Successful anti-TNFalpha treatment in a child with posttransplant recurrent focal segmental glomerulosclerosis.Am J Transplant. 2009; 9: 858-861Crossref PubMed Scopus (48) Google Scholar A recent report showed a significant effect of abatacept, a costimulation blocker, in 4 patients with recurrent FSGS where it induced partial or complete remission. The use of abatacept attempts to leverage the inducible expression of B7-1 on the podocyte, and its suppression may stabilize ß1 integrin activation.46Yu C.C. Fornoni A. Weins A. et al.Abatacept in B7-1-positive proteinuric kidney disease.N Engl J Med. 2013; 369: 2416-2423Crossref PubMed Scopus (295) Google Scholar Our current approach to allograft recipients with FSGS consists of a lympho-depleting induction therapy containing antithymocyte globulin at the time of transplantation followed by close monitoring of proteinuria. If proteinuria develops, we seek confirmation of diffuse podocyte effacement or FSGS lesions by biopsy. We prefer intensive treatment with plasmapheresis and higher dose maintenance of steroids and rituximab, followed by gradual tapering of plasmapheresis depending on the proteinuric response. Although not universally successful in eliminating the need for long-term plasmapheresis, we have obtained complete remission in most cases, even when the recurrent disease is very severe, including the need for transient dialysis. In our opinion, treatment of FSGS recurrence should be attempted in all such cases, and we consider unnecessary the removal and retransplantation of the allograft even in most severe cases. Among patients with a primary glomerulonephritis cause of ESRD, FSGS recurrence doubled the risk of allograft failure in a consortium study in the United States.47Hariharan S. Adams M.B. Brennan D.C. et al.Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR).Transplantation. 1999; 68: 635-641Crossref PubMed Scopus (212) Google Scholar A very similar doubling of the risk of allograft failure because of FSGS recurrence was observed in a cohort of kidney transplant recipients from Australia and New Zealand.48Briganti E.M. Russ G.R. McNeil J.J. Atkins R.C. Chadban S.J. Risk of renal allograft loss from recurrent glomerulonephritis.N Engl J Med. 2002; 347: 103-109Crossref PubMed Scopus (437) Google Scholar In the same cohort, FSGS recurrence accounted for 12.7% of allograft loss at 10 years after transplantation. In a French cohort of 33 patients with FSGS, the 5-year graft survival was substantially lower in the recurrence group at 57% vs 82% in those kidney transplant recipients without recurrence.4Pardon A. Audard V. Caillard S. et al.Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients.Nephrol Dial Transplant. 2006; 21: 1053-1059Crossref PubMed Scopus (79) Google Scholar In a retrospective analysis from the Scientific Registry of Transplant Recipients, possibly more prone to the misclassification of FSGS, its recurrence accounted for 18.7% of living-donor and 7.8% of deceased-donor allograft loses.49Abbott K.C. Sawyers E.S. Oliver J.D. et al.Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States.Am J Kidney Dis. 2001; 37: 366-373Abstract Full Text PDF PubMed Scopus (101) Google Scholar In general, the outcomes of recurrent FSGS are even worse in the pediatric population, particularly for early recurrent disease.8Baum M.A. Outcomes after renal transplantation for FSGS in children.Pediatr Transplant. 2004; 8: 329-333Crossref PubMed Scopus (75) Google Scholar The living donation, particularly living related, which is more prevalent in the pediatric population is also associated with an increased risk of recurrence; however, it is unclear if the recurrence of FSGS is correlated with an increased risk of graft failure compared with deceased donors, likely because of the additional benefits of living-donor transplantation.8Baum M.A. Outcomes after renal transplantation for FSGS in children.Pediatr Transplant. 2004; 8: 329-333Crossref PubMed Scopus (75) Google Scholar, 49Abbott K.C. Sawyers E.S. Oliver J.D. et al.Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States.Am J Kidney Dis. 2001; 37: 366-373Abstract Full Text PDF PubMed Scopus (101) Google Scholar The severity of the clinical presentation, particularly in relation to the level of proteinuria and graft dysfunction, response to treatment employed, and the presence of risk factors, contributes significantly to the outcome of recurrent FSGS. FSGS recurrence remains a heterogeneous disease in relation to its etiology, clinical and histologic manifestations and response to treatment. Recent advances in the understanding of etiology and pathogenic mechanisms have significantly improved disease classification, which may lead to a clearer determination of the risk of recurrence for primary FSGS in the future. Advancements in the podocyte biology and functional mechanisms may identify additional targets for treatment. Although successful outcomes have been reported not infrequently, recurrent FSGS in the renal allograft remains a significant problem in transplantation and continues to affect long-term graft survival.