Transplant Glomerulopathy Patients Research Articles

Clinical, Histological, and Molecular Markers Associated With Allograft Loss in Transplant Glomerulopathy Patients.

We aimed to investigate the clinical, histopathological, and molecular factors associated with allograft loss in transplant glomerulopathy (TGP) patients. Of the 525 patients who underwent clinically indicated kidney biopsies, 52 (10%) had diagnosis of TGP. Gene expression profiles of 28 TGP and 11 normal transplant kidney biopsy samples were analyzed by Affymetrix HuGene 1.0 ST expression arrays. Over a median follow up of 23 months (1-46 months) after the diagnosis of TGP by biopsy, 17 patients (32%) lost their allografts at a median of 16 months (1-44 months). There was no difference between the 2 groups in terms of any demographic variables, serum creatinine, panel reactive antibody levels, donor-specific antibody frequency, or mean fluorescence intensity values. Patients who lost their allograft had a significantly higher median spot protein to creatinine ratio 2.81 (1.20-6.00) compared to no graft loss patients 1.16 (0.15-2.53), (P < 0.01), and a trends toward a higher mean chronic glomerulopathy (cg) score (1.65 ± 0.93 vs 1.11 ± 0.93) (P = 0.05). There was also no difference in microvascular inflammation or any other Banff injury scores between the 2 groups. Although 117 gene transcripts were upregulated in both groups, 86 and 57 were upregulated in graft loss and functioning allograft groups, respectively. There were significantly increased levels of intragraft endothelial cell-associated transcripts, gene transcripts associated with complement cascade, interleukins and their receptors and granulysin in graft loss patients compared to patients with a functioning allograft. Our results demonstrate differential intragraft gene expression profiles in TGP patients with allograft loss.

Antibody Response Against the Glomerular Basement Membrane Protein Agrin in Patients with Transplant Glomerulopathy

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.

Antibodies reactive with agrin in transplant glomerulopathy

O427* Aims: About 15% of the patients with chronic renal allograft rejection show characteristics of chronic transplant glomerulopathy (TGP), including duplications of the glomerular basement membrane (GBM). We hypothesized that humoral immune responses are involved in TGP. Methods : We selected 18 cases with TGP showing double contours of the GBM on light microscopy. Patients with chronic rejection were used as controls. Paraffin sections were stained with polyclonal C4d antibodies. Sera of 13/18 patients were tested for anti-HLA and antibodies reactive with GBM. Results: Glomerular C4d deposits were present in a capillary pattern in 10/11 biopsies with TGP and in only 2/13 controls. Donor-specific anti-HLA antibodies were demonstrated in 6/13 patients and in 2/9 controls. Antibodies reactive with GBM isolates were detected in 9/13 patients and in 2/10 controls, but not directed to the Goodpasture antigen. Immuno-affinity purification yielded a large antigen. All patients with GBM reactivity had antibodies to this antigen. An antibody directed to the heparin sulphate proteoglycan (HSPG) agrin recognized the purified antigen. Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and co-localization with agrin. Conclusions: In TGP patients, glomerular C4d deposits were found, together with serum antibodies reactive with GBM isolates, suggesting a humoral tissue-specific immune response. Purified antigen was recognized by anti-agrin. A similar linear GBM staining pattern of patient sera and anti-agrin supported the potential role of the HSPG agrin in TGP.