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Podocyte Effacement Closely Links to suPAR Levels at Time of Posttransplantation Focal Segmental Glomerulosclerosis Occurrence and Improves With Therapy

Alachkar, Nada1,7; Wei, Changli2; Arend, Lois J.3; Jackson, Annette M.1; Racusen, Lorraine C.3; Fornoni, Alessia4; Burke, George5; Rabb, Hamid1; Kakkad, Kavita6; Reiser, Jochen2,7; Estrella, Michelle M.1

doi: 10.1097/TP.0b013e31829eda4f
Clinical and Translational Research
Free

Background Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30% of cases and can lead to allograft loss. Serum soluble urokinase-type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS.

Methods We conducted a retrospective study of 25 adults with posttransplantation FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function, and resolution of histologic changes.

Results A median (interquartile range) of 15 (10–23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pretreatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4806 pg/mL; P=0.02). Overall, mean±SD of proteinuria improved from 5.1±3.8 to 2.1±2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57%±33% to 22%±22% (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6–44.2) to 39.3 (28.8–63.4; P<0.0001), and suPAR levels decreased from a median of 6.781 to 4.129 pg/mL (P=0.02) with therapy.

Conclusions Podocyte effacement is the first pathologic manifestation of FSGS after transplantation. The degree of podocyte effacement correlates with suPAR levels at time of diagnosis. Response to therapy results in significant reduction of suPAR levels and complete or significant improvement of podocyte effacement.

1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

2 Department of Medicine, Rush University Medical Center, Chicago, IL.

3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.

4 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL.

5 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL.

6 Department of Medicine, Union Memorial Hospital, Baltimore, MD.

7 Address correspondence to: Nada Alachkar, M.D., Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 971, Baltimore, MD 21205 and Jochen Reiser, M.D., Ph.D., Department of Medicine, Rush University Medical Center, Cohn Research Building, Suite 724, 1735 W. Harrison Street, Chicago, IL 60612.

J.R. was supported in part by the National Institutes of Health (NIH) grants DK073495 and DK089394. A.F. was supported by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK090316 and by the Nephcure Foundation. M.M.E. was supported by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant 1K23DK081317.

C.W. and J.R. are inventors on pending or issued patents related to novel antiproteinuric strategies and therapeutics. All other authors declare no conflicts of interest.

E-mail: nalachk1@jhmi.edu and jochen_reiser@rush.edu

N.A., J.R., and M.M.E. participated in the research design, writing of the article, performance of the research, and data analysis. C.W. participated in the suPAR measurements and analysis and writing of the article. L.J.A. provided the pathology images and participated in the writing of the article. A.M.J. provided patients’ sera for suPAR measurements and participated in the writing of the article. L.C.R. participated in the writing of the article and review of pathologic data. A.F., G.B., and H.R. participated in the writing of the article. K.K. participated in the collection of clinical data.

Received 10 May 2013. Revision requested 17 April 2013.

Accepted 3 June 2013.

Accepted July 10, 2013

Primary focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease in the United States (1) and recurs after kidney transplantation in approximately one-third of cases (2) and up to 64% of high-risk patients (3). Recurrence of FSGS is associated with increased risk for renal allograft failure (4).

Loss of podocyte structural integrity and function is thought to be the central abnormality leading to FSGS. Circulating permeability factors likely play a major role in the pathogenesis of primary and recurrent FSGS (5). Recently, compelling evidence suggests that the soluble urokinase-type plasminogen activator receptor (suPAR) is one of these causative permeability factors (6). In two studies by Wei and colleagues (6, 7), the majority of participants with primary FSGS had significantly higher levels of suPAR compared with those with other glomerular diseases. Furthermore, patients with recurrent FSGS had higher levels of suPAR before transplantation and during the course of FSGS recurrence after transplantation (6). In animal models, circulating two domain suPAR (D1-D2) activated podocyte β3 integrin leading to podocyte foot process effacement, proteinuria, and FSGS-like histopathology (6).

Prior case series implicated that minimal change-like histopathologic changes may precede classic FSGS lesions in native and transplanted kidneys (8, 9). Moreover, foot process effacement can be observed as early as 1 hr after reperfusion in those who ultimately developed recurrent FSGS (10). Although successful management of FSGS recurrence using plasmapheresis with or without adjunctive rituximab is assumed to be associated with rapid resolution of podocyte foot process effacement (11), there have been only limited data to support that (12). Thus, the purpose of this study was to detail the evolution of renal histopathologic and ultrastructural changes and evaluate renal parameters, including serum suPAR levels, in 25 individuals who received plasmapheresis with or without rituximab for FSGS after kidney transplantation.

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RESULTS

Clinical Characteristics

Table 1 displays the sociodemographic and clinical characteristics of the study population with posttransplantation recurrent and de novo FSGS (n=25). Mean follow-up duration is 15.6±10.6 months. Recurrent FSGS patients (n=21) were drawn from a population of 105 adult renal transplant recipients aged 18 years or older with FSGS in the native kidney (93 biopsy-proven and 12 with probable FSGS), with approximate recurrence rate of 20%. Among the seven patients with previous kidney transplantation, five lost their previous allografts due to recurrent FSGS and two due to other causes.

TABLE 1

TABLE 1

The median (interquartile range [IQR]) time to recurrent or de novo FSGS was 31 (5–225 days) after transplantation. Nine of recurrent FSGS patients had histopathologic data available on their primary FSGS: three had collapsing, two had tip, and four had classic (not otherwise specified) FSGS variant (13). Of these individuals, four had histopathologic data also available at the time of recurrence: three had concordant FSGS variants and one subject who had primary classic FSGS had recurrent collapsing FSGS after transplantation.

Before treatment, 23 (92%) subjects of our cohort had estimated glomerular filtration rates (eGFR) below 60 mL/min/1.73 m2. Fourteen subjects had 3 g/g or more of proteinuria; 5 of them had serum albumin levels below 3.5 g/dL. Data on serum lipid levels and presence of edema were not available to ascertain whether nephrotic syndrome was present in these patients.

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Baseline Pathologic Changes and Correlation With suPAR Levels

Twenty-four subjects had renal biopsies available at time of posttransplantation FSGS diagnosis; of these, 6 were obtained shortly after the initiation of therapy (mean [range] after treatment initiation, 5 [3–9] days). On baseline renal biopsy, six of the subjects had histopathologic changes consistent with FSGS on light microscopy (two with classic FSGS, one with tip and collapsing variant, two with collapsing variant, and one with perihilar variants), whereas 18 did not have any FSGS changes on light microscopy. Overall foot process effacement ranged from 13% to 100%.

Among subjects with renal biopsies available at diagnosis, pretreatment suPAR levels were measured in 16 patients; 5 of them had 25% or less and four had 75% or more of foot process effacement. suPAR levels significantly correlated with the severity of foot process effacement at baseline (r2=0.70; P=0.01). The median (IQR) pretreatment suPAR levels were more than twofold higher among those with severe (≥75%) versus those with mild (≤25%) foot process effacement (13,030 [7679–17,858] vs. 4806 [4450–5961] pg/mL, respectively; P=0.02), although their median (IQR) eGFR levels were similar (22.3 [15.7–51.9] vs. 37.9 [28.0–43.8] mL/min/1.73 m2, respectively; P=0.62).

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Treatment Outcomes

Twenty-four subjects underwent plasmapheresis with a median (IQR) of 15 (10–23) sessions received. One patient received only intensification of maintenance immunosuppression. Thirteen subjects were refractory to plasmapheresis and received adjunctive rituximab infusion. Nine (36%) subjects achieved complete remission, and 10 (40%) individuals achieved partial remission.

Twenty patients had at least one follow-up biopsy, of which 15 were after full completion of the therapy. On follow-up biopsy, five of the subjects who had baseline light microscopic FSGS changes continued to have the same changes. Seven additional patients developed light microscopic FSGS changes on follow-up biopsies (four collapsing variant, one tip variant, and two classic FSGS). Four of these seven patients were refractory to therapy and three had only partial response to therapy. Of the four refractory cases, three had allograft loss shortly after the FSGS recurrence. Of the three subjects who had partial response and subsequent FSGS changes on light microscopy, one had allograft failure after 1 year of the diagnosis.

The median (IQR) time between the end of treatment and posttreatment suPAR, serum creatinine, proteinuria, and foot process assessments were 8 (2–52), 0 (0–1), 2 (0–19), and 25 (10–33) days, respectively. The median (IQR) time between the end of treatment and the most recent available proteinuria measurement was 233 (127–381) days.

Although the median eGFR improved significantly from 32.9 to 39.3 mL/min/1.73 m2 (P<0.0001) with treatment, the overall median (IQR) serum creatinine, although improved from 2.3 (1.7–3.3) to 1.9 (1.5–2.3), did not reach statistical significance (P=0.08; Table 2; Fig. 1A).

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

Overall mean proteinuria decreased significantly from 5.1±3.8 g/g during pretreatment to 2.1±2.8 g/g during posttreatment (P=0.003); this decrease was observed primarily among subjects who received rituximab in addition to plasmapheresis (Table 2). Among those who attained complete or partial remission (Table 3), mean pretreatment to posttreatment proteinuria declined significantly from 5.3±3.9 to 1.5±1.7 g/g (P=0.0005; Fig. 1B). This improvement persisted on the last available proteinuria measurements (mean peak to last available, 8.8±7.0 to 1.7±2.6 g/g; P=0.0002; Table 3). In contrast, individuals who did not respond to treatment (n=6) had persistent proteinuria, with a posttreatment mean proteinuria of 15.1±18.7 g/g.

TABLE 3

TABLE 3

The overall suPAR levels decreased from a median of 6.781 to 4.129 pg/mL (P=0.02) with treatment (Table 2; Fig. 1).

Improvements in these clinical parameters correlated with remarkable improvement in foot process effacement, which decreased from 55%±34% to 22%±23% (P=0.0009; Fig. 1C) in subjects who achieved complete or partial remission. Furthermore, the improvement in podocyte foot process effacements involved even patients who failed to respond to therapy in respect to proteinuria (Fig. 2).

FIGURE 2

FIGURE 2

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C-Reactive Protein Levels in Individuals With Posttransplantation FSGS

To evaluate the association between suPAR and inflammation in posttransplantation FSGS subjects, C-reactive protein (CRP) levels were measured in 15 individuals with posttransplantation FSGS at time of diagnosis. Mean CRP levels were low (9.8±4.3; reference range, 0–20) in these patients (Table 1).

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DISCUSSION

Our study confirmed that the first pathologic finding of recurrent renal allografts is podocyte foot process effacement. We demonstrated that circulating suPAR levels at the time of diagnosis correlate with the severity of effacement. Furthermore, a complete or even partial response to therapy results in significant resolution of foot process effacement and improvement in proteinuria. In the seven patients with suPAR measured before and after therapy, we noted a significant decrease in the levels after therapy.

Early reports implicated the importance of podocytes in the recurrence of FSGS after transplantation. Harrison et al. reported a case of a 62-year-old woman who suffered recurrent FSGS (14). Biopsies of native kidney and at the time of posttransplantation recurrence showed similar alterations in the podocyte junctions. Hoyer et al. reported in 1972 that minimal change disease preceded FSGS recurrence in two cases (15). In a report of a patient with immediate recurrent FSGS, the allograft biopsy at 1 hr after transplantation showed minor glomerular abnormalities with partial foot process effacement on electron microscopy (16). We also recently reported on 19 pairs of prereperfusion and postreperfusion biopsy results obtained from patients with FSGS undergoing renal transplantation (10). The mean number of effaced foot processes on the postreperfusion biopsy was higher among the seven subjects who developed recurrent FSGS within 30 days compared with those who did not. Cheong et al. also reported on six children with early FSGS recurrence, five of them had only foot process effacement initially. However, three of them later developed segmental sclerosis on subsequent renal biopsies (17). Our study, which represents the largest sample to date, confirms that the earliest detectable ultrastructural change in recurrent FSGS after renal transplantation is podocyte foot process effacement.

Whether these podocyte changes resolve with treatment, however, has not been well delineated in the current literature. Artero et al. reported on their 10-year experience of recurrent FSGS in adults and children (12). They noted one individual whose foot process effacement resolved with plasmapheresis accompanied by decline in proteinuria and three who achieved remission with treatment had only podocyte changes, whereas two who did not respond to therapy already had sclerosis before plasmapheresis. The recent case report by Gallon et al. in which an allograft from a recipient with early FSGS recurrence was subsequently retransplanted to a different patient without primary FSGS supports the reversibility of foot process effacement in FSGS. These changes resolved on postoperative day 14 (18). In our study, we found that our therapy resulted in significant improvement in podocyte effacement decreasing from a mean of 55% to 22%. The decrease in podocyte effacement involved not only responders but also patients who did not respond to therapy by way of a significant decrease in proteinuria. These improvements may be due to the early recognition of FSGS recurrence and institution of therapy.

Furthermore, we found that suPAR levels correlated significantly with the degree of the ultrastructural changes in podocytes. In line with such a quick correction of podocyte ultrastructure are observations from a mother with FSGS who gave birth to a child with transient proteinuria (19). Both mother and child had high suPAR blood levels; the baby’s resolution of proteinuria is likely due to the decrease of suPAR serum levels and correction of podocyte injury.

In our study, posttransplantation CRP levels were normal, arguing against the contribution of inflammation to the high suPAR levels observed among our posttransplantation FSGS subjects. However, CRP represents only one marker of the activity of inflammatory pathways, and further analysis is needed.

Although clinical improvement among recipients with posttransplantation FSGS associated with treatment may have been mediated by plasmapheresis-related declines in suPAR, rituximab was found by Fornoni et al. to have direct stabilizing effects on podocyte function (3). Taken in the context of variable response to plasmapheresis with or without rituximab and the fact that suPAR binds and activate β3 integrin expressed on podocytes (6), prospective studies are needed to determine whether the gene expression that encodes for β3 integrin (ITGB3) in the recipient or allograft kidney (20) also has prognostic bearing on recurrent FSGS and response to treatment.

In spite of these significant findings of our study, it has a few limitations. Our main limitation was the retrospective design of our study, which may have led to missing some important cofounders that could have influenced our results. Although a prospective study in this field will be of great importance, our overall findings will have significant clinical application in kidney transplant recipients with posttransplantation FSGS. In addition, our study size was small, and findings reflect the clinical practice of a single center; therefore, our results may not be generalizable to other renal transplant centers. Furthermore, our study lacks control groups with nonrecurrent FSGS or non-FSGS patients. This was in most part due to the limited available sera obtained at the same time points (as per our study methods) for suPAR measurements, in addition to incomplete clinical data on these individuals. Finally, although median suPAR levels exceeded 3000 pg/mL, reported as the threshold to discriminate between FSGS cases and other nephrotic syndromes, these data were reported in a population composed primarily of individuals with primary FSGS (6, 7). Thus, this threshold may not be applicable for posttransplantation FSGS.

In summary, early posttransplantation recurrent or de novo FSGS manifests histologically by podocyte foot processes effacement. Response to therapy with plasmapheresis with or without rituximab may prevent light microscopic changes of FSGS from developing. suPAR may be one of the main circulating permeability factors that cause recurrent FSGS via binding to the podocytes. However, larger and multicenter prospective studies are needed to clarify the utility of suPAR measurements in predicting FSGS recurrence after transplantation and in monitoring response to therapy.

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MATERIALS AND METHODS

The study was approved by the Johns Hopkins Medicine Institutional Review Board (Baltimore, MD). This is a retrospective case series study of all adult renal transplant recipients who underwent renal transplantation between January 1, 2003 to December 31, 2011 in our center and developed recurrent or de novo FSGS after kidney transplantation. Twenty-five individuals included in this study developed FSGS after transplantation.

All subjects received thymoglobulin and high-dose steroid for induction and a three-drug regimen consisting of mycophenolate mofetil, tacrolimus, and prednisone for maintenance immunosuppressions. Four patients with recurrent FSGS were switched from tacrolimus to cyclosporine during their treatment course for FSGS. None of the subjects received sirolimus.

Recurrent FSGS was defined by the presence of proteinuria as measured by urine protein-to-creatinine ratio and confirmed by 24-hr urine collection. A ratio of greater than 1 g/g in individuals who were anuric before renal transplantation (n=8) or a persistent increase in urine protein-to-creatinine ratio by greater than 1 g/g from baseline proteinuria among those who made urine before renal transplantation (n=16) was consistent with the diagnosis (data of urine before transplantation was not available on one patient). The diagnosis was confirmed by histologic findings of FSGS on biopsies obtained before or within 10 days of treatment commencement. On the contrary, de novo FSGS posttransplantation was defined by (a) new onset of more than 1 g/g proteinuria (or +2 on urinalysis in one patient with unavailable urine protein-to-creatinine ratio at time of diagnosis) in recipients whose primary cause of end-stage renal disease was not attributed to FSGS (n=2, IgA nephropathy and lupus nephritis) or was unknown (n=2, native kidney biopsy was not performed) in addition to (b) allograft biopsy with light microscopic changes consistent with FSGS, which is not explained by other pathologic findings.

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Data Collection

Sociodemographic and clinical data were abstracted from patient medical records from the time of renal transplantation to 3 years after renal transplantation or the latest available clinical follow-up. Donor clinical characteristics included donor vital status, relatedness to the recipient, and ABO-compatibility with the recipient. Recipient clinical characteristics included age at FSGS diagnosis, number of prior renal transplantations, duration of dialysis, serum creatinine, and proteinuria estimated by urine protein-to-creatinine ratio. eGFR was measured using the CKD-Epi equation, which adjusts for the variation in serum creatinine associated with age, gender, and race (21).

Treatment with plasmapheresis was initiated at the time of diagnosis. A 100% albumin replacement fluid was routinely used. We used fresh-frozen plasma when patients were to undergo a renal allograft biopsy within 48 hr or in cases of daily plasmapheresis. One or two rituximab infusions (dose of 375 mg/m2 of body surface area) were administered to patients who failed to achieve complete or partial remission with plasmapheresis therapy alone. Complete remission was defined by a decrease in proteinuria to below 1 g/g upon completion of the treatment course. Partial remission was defined as a decline in proteinuria by 50% from the peak proteinuria level but remaining 1 g/g or greater at the end of therapy.

Renal histopathology was assessed by a renal pathologist using light microscopy, immunofluorescence, and electron microscopy. The degree of podocyte foot process effacement was based on biopsy reports as well as second assessments of the electron microscopy by another renal pathologist blinded to the original biopsy report and the recipient’s outcome. These two assessments were then averaged to obtain the mean podocyte foot process effacement, which was then categorized into mild (≤25%), moderate (26%–74%), and severe (≥75%). Baseline electron microscopy results were obtained from renal biopsies performed before or within 10 days of initiating therapy. Posttreatment foot process effacement was assessed from renal biopsies performed after the completion of the plasmapheresis sessions and rituximab infusion in refractory cases. A minimum of 10 capillaries was used to determine podocyte effacement.

Among recipients with stored sera available before and after treatment, suPAR levels and CRP levels were measured. suPAR levels were measured by using Quantikine Human uPAR immunoassay (R&D Systems, Minneapolis, MN), whereas CRP was measured by using Quantikine ELISA kit (R&D Systems). Individuals who underwent ABO-incompatible transplantation were excluded from the suPAR and CRP analyses.

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Statistical Analysis

We performed descriptive analyses to evaluate the distribution of the recipients’ baseline sociodemographic and clinical characteristics. The Kruskal–Wallis test was used to compare medians of nonnormal continuous variables across categories, whereas the Mann–Whitney U test was used to compare means of normally distributed variables across categories. Pretreatment and posttreatment comparisons were performed using paired t test and the Wilcoxon sign-rank test, as appropriate. Comparisons of pretreatment and posttreatment clinical parameters were conducted using the overall study population and then restricted only to recipients who attained complete or partial response to treatment. All statistical analyses were performed using Stata/MP version 11.2 (StataCorp, College Station, TX).

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ACKNOWLEDGMENT

The authors thank Rachel Marino, NP, for her help in collecting some of the clinical data.

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Keywords:

Kidney transplant; Podocyte effacement; FSGS; suPAR; Rituximab

© 2013 by Lippincott Williams & Wilkins