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Transplant Glomerulopathy May Occur in the Absence of Donor-Specific Antibody and C4d Staining

Enver Akalin^*,, Rajani Dinavahi^*,, Steven Dikman, Graciela de Boccardo^*,, Rex Friedlander, Bernd Schroppel^*,, Vinita Sehgal^*,, Jonathan S. Bromberg, Peter Heeger^*,, and Barbara Murphy^*,

^* Renal Division, Recanati/Miller Transplantation Institute, and Department of Pathology, Mount Sinai School of Medicine, and Immunogenetics Laboratory, Rogosin Institute, New York, New York

Correspondence: Dr. Enver Akalin, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1104, New York, NY 10029-6574. Phone: 212-659-8086; Fax: 212-348-2474; E-mail: enver.akalin{at}msnyuhealth.org

	Abstract

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Background and objectives: Transplant glomerulopathy (TGP) has been proposed to be a component of chronic antibody-mediated rejection (AMR). We have studied 36 patients with TGP and 51 patients with chronic allograft nephropathy (CAN) but without TGP for C4d staining and donor-specific anti-HLA antibodies (DSA) to investigate the alloantibody-mediated mechanisms.

Design, setting, participants, & measurements: Allograft biopsies were stained with C4d staining and DSAs were studied by Luminex Flow Beads. Allograft biopsies were done at a mean of 5.3 ± 5.0 and 5.6 ± 4.6 yr after transplantation in patients with CAN and TGP, respectively.

Results: The mean creatinine level at the time of the biopsy was 2.7 ± 1.2 mg/dl in each group. Proteinuria of >1.0 g/d was more common in patients with TGP (61 versus 25%; P = 0.002). Whereas three patients with TGP had a history of acute AMR, none of the patients with CAN had. Mean chronicity score of the biopsies were 1.7 ± 0.7 in patients with CAN and 1.9 ± 0.8 in patients with TGP. Biopsies from only two (4%) patients with CAN and four (11%) patients with TGP had diffuse C4d positivity. DSA were found in 36% of TGP and 33% of CAN patients.

Conclusions: These results suggest that a substantial number of patients with TGP did not have positive C4d staining or DSA, indicating that a non-alloantibody-mediated process may be involved in the development of TGP in some patients.

	Introduction

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Transplant glomerulopathy (TGP), also called chronic allograft glomerulopathy, is a distinctive glomerular lesion that is unique to renal allografts and is characterized on light microscopy by capillary wall widening and double contours that enclose a clear zone that is often contiguous with a pale expanded mesangium (Figure 1A). On electron microscopy, the thick double glomerular capillary outlines are due to flocculent material on the subendothelial aspect with an underlying layer of new basement membrane material (Figure 1B). This is distinguished from mesangiocapillary (membranoproliferative) glomerulonephritis by the absence of mesangial proliferation and lack of immune deposits by immunofluorescence and electron microscopy. The prevalence varies from 2 to 7% of all renal transplant biopsies and 10 to 30% of the biopsies with chronic allograft nephropathy (CAN) or glomerular disease (1–4). TGP can be diagnosed by electron microscopy alone in some patients; therefore, the prevalence can be higher in series using electron microscopy. Clinically, patients with TGP have more proteinuria and decreased graft survival compared with patients with CAN and without TGP (1–4).

View larger version (79K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. (A) Light microscopy of transplant glomerulopathy (TGP) showing numerous glomerular capillary walls with double contours enclosing a clear to flocculent region. (B) Electron microscopy of TGP showing widening of the subendothelial aspect of capillary walls by pale to flocculent proteinaceous material and one or more lamella of basement membrane material beneath the endothelial cell lining. One capillary also contains cell interposition between the basement membrane and endothelium. (C) C4d in chronic allograft showing area of parenchymal scarring and diffusely positive reaction in interstitial capillaries. Magnifications: x400 in A (periodic acid-Schiff stain); x3000 in B; x200 in C (immunoperoxidase method).

Because of these controversial results in the published literature, we retrospectively evaluated our own data of 87 renal allograft recipients with CAN—36 had TGP and 51 did not—and found no strong association with humoral alloimmunity. The findings suggest that the pathogenesis of TGP does not always require humoral alloimmunity and have important implications for appropriately interpreting allograft biopsies with chronic injury.

	Concise Methods

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Patients
Since July 2003, we have routinely stained all transplant kidney biopsies for C4d, and patients with history of sensitization, including previous transplantation, blood transfusion, or pregnancy, are tested for circulating DSA by Flow Specific Beads (One Lambda, Canoga Park, CA). Biopsies were performed for worsening renal function and/or proteinuria. Of the 428 transplant kidney biopsies on which C4d staining was performed, 51 patients with CAN and 36 with TGP and CAN on biopsies were identified. Patients’ demographics and clinical information including age, gender, race, transplant source and date, donor age and gender, panel reactive antibody titers, serum creatinine, proteinuria, previous acute rejection episodes, type of immunosuppressive therapy, and current graft function were obtained from hospital charts and laboratory records. The study and data collection were reviewed and approved by the institutional review board of Mount Sinai School of Medicine.

Histopathology and C4d Staining
All biopsy specimens were examined by light microscopy (hematoxylin and eosin, periodic acid-Schiff, and trichrome stain) and in addition with immunofluorescence and electron microscopy when the patients had proteinuria. All histologic lesions were classified and scored according to the Banff 97 classification (11). CAN biopsies were graded as grade I (mild), grade II (moderate), and grade III (severe) according to the severity of chronic transplant glomerulopathy (cg), interstitial fibrosis, transplant arteriopathy, and arteriolar hyalinosis. TGP was characterized by reduplication or "double contours" formation of the glomerular basement membrane on light microscopy. Severity of TGP was graded as mild (cg1), moderate (cg2), and severe (cg3) by the extent of double contours in the most severely affected of nonsclerotic glomeruli. Electron microscopy was characterized by widening of the subendothelial electron-lucent flocculent material and an underlying layer of new basement membrane material. There may be mesangial interposition into the capillary wall, but immune-type electron-dense deposits were absent.

C4d staining was performed on paraffin sections using polyclonal rabbit anti-C4d antibody (Rabbit Polyclonal, cat. no. 12-5000; American Research Products, Belmont, MA). Paraffin-embedded tissue sections were deparaffinized and rehydrated by passage through 2 x 5-min soaks in xylenes, followed by 2 x 5-min soaks in 100% ethanol, followed by 2 x 5-min soaks in 90% ethanol. The slides were then rinsed with copious amounts of deionized water. Endogenous peroxidases were blocked by incubation of the slides for 15 min at room temperature in 3% aqueous hydrogen peroxide, followed by rinsing with copious amounts of water. Slides were then subjected to microwave antigen retrieval: Slides were placed in a slide container of 1 mM EDTA that was heated just to boiling in a microwave. The microwave was run on high until the solution just came to a boil again. The power was then decreased so that the solution would boil for 10 s of every minute for 20 min. The slides were allowed to cool for another 20 min and then rinsed with deionized water. All slides were soaked at room temperature for 5 min in Tris-buffered saline (pH 7.6) that contained 0.05% Tween 20 (TBST; DAKO Corp, Carpinteria, CA) and placed in a DAKO Autostainer. The slides were incubated for 30 min at room temperature with a 1:30 dilution of anti-C4d in 2% BSA in PBS (pH 7.4). The Autostainer then rinsed the slides with TBST, incubated them for 30 min at room temperature with EnVision + polymer (polymerized, peroxidase-conjugated second antibody directed against rabbit primary antibodies; DAKO), rinsed them with TBST, and incubated them for 10 min at room temperature with diaminobenzidine tetrahydrochloride (DAB) substrate solution (DAKO) followed by a final deionized water wash. The slides were then removed from the Autostainer; counterstained with hematoxylin; rinsed in water until the solution was free of hematoxylin, 2 x 5 min in 90% ethanol, 2 x 5 min in absolute ethanol, and 2 x 5 min in xylenes; and coverslipped.

C4d staining was scored as positive (or diffuse positive) when there was uniform finely granular decoration involving >50% of the peritubular capillaries (Figure 1C). Focal C4d positivity was defined when 10 to 50% of the sampled capillaries were involved. C4d staining of the glomeruli was not evaluated.

Detection of Anti-HLA Antibodies
Anti-HLA antibodies were studied by Luminex Flow Beads (LABScreen products from One Lambda, Canoga Park, CA) at Rogosin Immunogenetics laboratory. It uses a panel of color-coded beads that are coated with purified HLA antigens. The patient's test serum was incubated with the beads, and any bound HLA IgG antibodies were subsequently labeled with R-phycoerythrin–conjugated goat anti-human IgG. The Luminex LABScan 100 flow analyzer detects the fluorescence emission from each bead, and the specificity of the IgG HLA antibodies were assigned.

Statistical Analyses
Clinical and demographic data of the patients with TGP and CAN were compared using the independent samples t test for continuous variables and ² test for categorical variables. P < 0.05 was considered significant. Graft survival was analyzed by Kaplan-Meier method.

	Results

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Clinical Features of Patients with CAN and TGP
There were 51 patients with CAN and 36 patients with TGP in addition to CAN findings on the allograft biopsies (Table 1). Among patients with TGP, there were more female patients (58%) as compared with the CAN group (41%) and more living donor recipients (67 versus 40%, respectively), but the difference was not statistically significant. There were no differences in patients’ age, race/ethnicity, panel-reactive antibody titers, previous transplantation, cold ischemia time, induction treatment, and donor age and gender in both groups. Allograft biopsies were performed at a mean of 5.3 ± 5.0 and 5.6 ± 4.6 yr after transplantation in patients with CAN and TGP, respectively. The mean creatinine level at the time of the biopsy was 2.7 ± 1.2 mg/dl in each group. Proteinuria, defined as >1.0 g/d in a 24-h urine collection or spot urine/protein creatinine ratio or urine dipstick >300 mg/dl, was more frequent in patients with TGP (61 versus 25%; P = 0.002). Previous biopsy-proven acute cellular rejection episodes were similar in both groups (10 versus 6%). Whereas three patients with TGP had a history of acute AMR, none of the patients with CAN had previous acute AMR episode. The majority of the patients were on triple immunosuppressive medications with calcineurin inhibitors (CNI), mycophenolate mofetil, and prednisone, with the remaining on double immunosuppression with CNI and prednisone.

Patients who received a transplant after 2000 have been routinely studied for DSA at the time of transplantation. Twenty patients with TGP and 36 patients with CAN had information about pretransplantation DSA. Three patients with TGP had pretransplantation DSA and received desensitization protocol with intravenous Ig, but two had early acute AMR. Another patient with TGP developed early AMR and DSA. DSA were diagnosed at the time of biopsy (median 5 yr; range 2 to 20 yr) in seven patients with TGP. Four of those patients developed de novo DSA, and the remaining three patients did not have information about pretransplantation DSA. None of the 36 patients who had CAN and were studied for anti-HLA antibodies at the time of transplantation had DSA. In the 10 patients with CAN, DSA was diagnosed at the time of biopsy (median 3 yr; range 1 to 10 yr). Of the 10 patients with CAN and DSA, seven developed de novo DSA and the pretransplantation DSA status of the remaining three patients is unknown.

Graft Outcome
Graft loss during the follow-up period was more frequent in patients with TGP, but the difference was not statistically significant. Twenty-eight percent of patients with TGP lost their allografts, whereas only 16% patients with CAN experienced graft loss. The mean time to graft loss after the biopsy was 1.1 ± 1.1 yr in patients with TGP compared with 0.7 ± 0.7 yr in patients with CAN.

	Discussion

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Our results show that most (60%) TGP developed in the absence of anti-HLA antibodies (DSA or non-DSA) and positive diffuse C4d staining, raising the possibility that the pathogenesis of this disease involves alternative mechanisms. One plausible explanation is that TGP may develop as a result of a T cell–mediated immune process. We (12) recently reported on the expression of chemokines, chemokine receptors, and co-stimulatory molecules by immunohistology in human renal transplant biopsies of patients with CAN. We found expression of the chemokines Mig (CXCL9) and IP-10 (CXCL10), the chemokine receptor CXCR3, and inducible co-stimulator by intraglomerular and periglomerular leukocytes in biopsies with CAN and TGP but not CAN alone, suggesting that the activation of effector T cells may play a role in the development of TGP. Furthermore, there are extensive animal and initial human data that T cell recognition of processed alloantigen via the indirect pathway is a key factor in initiating and maintaining the progression of chronic allograft rejection (13–16). In addition, humoral alloimmunity and isotype switching to IgG is dependent on indirect alloreactivity (17,18). Thus, T and B cell involvement may not be two separate or exclusive processes but rather may cooperate with each other. These findings may suggest that C4d^–/DSA^– TGP can develop through cellular immune response and be classified under chronic T cell–mediated rejection, as CAA was classified in Banff 2005.

The frequency of anti-HLA antibodies detected after kidney transplantation is variable, ranging between 1.6 and 60%, depending on the method used or the type of patient population analyzed (19); however, not all patients with de novo DSA develop TGP, indicating not only that TGP may develop through B cell–mediated immune mechanisms but also that other factors, such as T cell help, may be involved in disease progression, along with antibody-mediated allograft damage. We (20) recently reported gene expression profiles of 16 transplant kidney biopsies by microarrays. None of the biopsies showed TGP, but one patient had both positive C4d staining and DSA. It is interesting that gene expression data from this patient revealed that >50% of the upregulated genes were related to Ig structures, complement, B cells (CD20), T cell receptor, nuclear factor of activated T cells, natural killer cells, cytokine receptors, chemokines, chemokine receptors, and B cell chemoattractants, indicating the possible importance of both cellular and humoral immune-mediated mechanisms in this particular patient.

There may be additional reasons for the development of TGP in the absence of DSA or C4d. Joosten et al. (21) showed that 11 of 16 patients with TGP have circulating antibodies reactive to glomerular basement membrane isolates, and seven of those patients demonstrated reactivity to agrin, a glomerular basement membrane antigen; however, it is not clear whether antibodies to agrin may play a role in the pathogenesis of TGP or whether patients develop antibodies to agrin or other glomerular basement membrane antigens only after the initial damage occurs through other factors. The possibility that TGP may develop from endothelial damage secondary to CNI must also be considered. Some of our patients’ biopsies demonstrated significant multinodular arteriolar hyalinosis while lacking C4d, circulating DSA, and/or a history of an acute rejection episode, raising the possibility that CNI may contribute to the pathogenesis of TGP.

One explanation for low prevalence of positive C4d staining in our patients with TGP could be that, because C4d deposition may be transient, C4d positivity may have been present at an earlier stage before biopsy and diagnosis of TGP. For example, one of the patients who developed CAN with positive C4d staining and de novo DSA was treated with intravenous Ig and initially responded to treatment with a reduction in proteinuria and loss of DSA (22). The patient subsequently developed TGP with reappearance of DSA; however, the biopsy was negative for C4d staining.

The failure to demonstrate DSA does not rule out the contribution of antibodies to the pathologic process, because absorption of antibodies by the allograft may result in a lack of circulating DSA. Martin et al. (23) investigated anti-HLA antibodies by FlowPRA (One Lambda) in 20 kidney transplant recipients who underwent transplant nephrectomy. Whereas 42% had DSA in their sera at 1 yr after transplantation and 32% at the time of nephrectomy, 74% of nephrectomy eluates and postnephrectomy serum samples showed DSA, demonstrating that in some cases anti-HLA antibodies were bound to the allograft and not detectable in the serum.

A recent study by Sis et al. (24) demonstrated that 73% of patients with TGP had anti-HLA antibodies or positive C4d staining. This is higher than our results (40%), but whereas 54% of their patients had a history of acute rejection, only 9% of our patients had previous acute rejection episodes, indicating that their patients might have developed TGP through more immune-mediated mechanisms. Gloor et al. (25) reported 22% TGP at 12-mo protocol biopsies of cross-match–positive kidney transplant recipients who received desensitization treatment and correlated with previous AMR by multivariate analysis. In our series, two patients who had early AMR and responded to treatment developed TGP later. Furthermore, although TGP mostly develops late after transplantation, occurring in our cohort of patients a mean of 5.6 yr after the transplantation, patients who had early AMR and did not respond completely to treatment may develop TGP early, as in the one patient whose biopsy at 3 mo after transplantation showed TGP.

Treatment of acute AMR often includes intravenous Ig, plasmapheresis or immunoadsorption, and Rituximab; however, it is unclear what the role is for these agents in the treatment of chronic AMR. We believe that some but not all patients develop TGP through antibody-mediated mechanisms with documented circulating DSA and positive C4d staining and may benefit from the reduction of circulating antibodies through anti–B cell therapies; however, some recipients almost certainly develop TGP through non–antibody-mediated mechanisms, and to classify TGP under the rubric of chronic active AMR may result in receipt of unnecessary treatments, which not only are expensive but also carry significant adverse effects, by patients who have TGP without DSA and/or C4d staining. Given our data and the varying results in the literature, we need to define more clearly the pathophysiologic processes that are involved in TGP. The studies to date all have been single-center, retrospective studies of clinically indicated biopsies. Our results indicated that TGP may result from endothelial damage caused by a variety of processes, including DSA, CNI, and chronic cellular immune injury, producing similar morphologic glomerular appearances. For clear definition of cases that are mediated by antibodies and also for determination of the contribution of T cell–mediated processes to this pathologic picture, large multicenter studies that conduct serial protocol biopsies along with monitoring of anti-HLA antibodies and cellular immunity must be performed to define the development of TGP and chronic AMR. These studies are currently the focus of several large National Institutes of Health–sponsored initiatives. The results of these studies may help to direct us toward appropriate specific and focused therapeutic interventions on an individual basis.

	Disclosures

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None.

	Acknowledgments

 
This study was presented at annual meeting of the American Transplant Congress; May 2007; San Francisco, CA.

	Footnotes

 
Published online ahead of print. Publication date available at www.cjasn.org.

See related editorial, "Chronic Transplant Glomerulopathy: Need for Further Assessment," on pages 1108–1109.

Received June 8, 2007. Accepted July 12, 2007.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: CJN.02420607v1 2/6/1261    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akalin, E. Articles by Murphy, B. Search for Related Content PubMed PubMed Citation Articles by Akalin, E. Articles by Murphy, B. Related Collections Related Article