Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York, NY, USA Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme a-galactosidase A (a-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified “renal variants” who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, “cardiac variants” who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant a-Gal A replacement for this inherited nephropathy.
Originals
Early progressive interstitial fibrosis in human renal allografts
H. Abo-Zenah, S. Katsoudas, D. de Takats, J. Shortland, G. Wild, C.B. Brown and A.M. El Nahas
H. Abo-Zenah, S. Katsoudas, D. de Takats, J. Shortland, G. Wild, C.B. Brown and A.M. El Nahas
1Sheffield Kidney Institute, 2Histopathology,
and 3Immunology Departments, Northern General Hospital Trust, Sheffield, UK Background: Early fibrosis has been described in renal allografts and implicated in the progression of chronic allograft nephropathy (CAN). The precise factors implicated in the initiation and progression of early allograft fibrosis remain uncertain. Patients and methods: We studied retrospectively 23 cadaveric renal allograft recipients over a 3-year period, who had paired renal biopsies (Bx) (at implantation and as clinically indicated) within 3 months of transplantation (Tx). Eight of them have progressed over an average period of 3.16 ± 0.83 years to CAN. Histological evaluation of interstitial fibrosis (IF) relied on point count analysis of Masson’s trichrome (MT) staining as well as immunostainable collagens III (iCol III) and IV (iCol IV). The severity of the IF scores was correlated with the clinical, biochemical and histological parameters. The nature and severity of the interstitial inflammatory infiltrate were also evaluated by immunofluorescence. In addition, patients were subdivided into those whose fibrosis progressed (> 50% increase in IF/iCol III; Group 1) and non-progressors (< 50% increase in fibrosis score; Group 2) in an attempt to determine discriminatory features. Results: In the whole group, there was a significant increase in the IF score, as estimated by MT staining and iCol III, from implantation to follow-up Bx (p = 0.0027 and p = 0.0088, respectively). The changes in iCol IV were not significant. Further, the increase in interstitial inflammatory infiltrate of total T lymphocytes, and not of macrophages, from implantation (modal category = 2) to follow-up (modal category = 0) was significant (p = 0.0121). The predictive value of such increase was significant (R2 = 0.617, p = 0.03). The donor’s age (R2 = 0.892, p = < 0.0001), death from cerebrovascular accident (CVA) (R2 = 0.822, p = 0.047), as well as recipient’s body weight (R2 = 0.892, p = 0.001), male gender (R2 = 0.687, p = 0.041) and elevated mean arterial pressure (MAP) (R2 = 0.892, p = < 0.0001) were all significant risk factors for early IF. Delayed graft function (DGF) proved to be a significant predictor of early IF (R2 = 0.822, p = 0.003) and became more significant in the presence of superimposed acute rejection (AR) (p = 0.0001). Proteinuria > 1 g/day (R2 = 0.882, p = 0.004) and hypertriglyceridemia > 2.25 mmol/l (R2 = 0.808, p = < 0.0001) were also associated with early IF. Of the implantation histological parameters, iCol III proved to be a highly significant predictor of early IF (R2 = 0.892, p = < 0.0001). Interestingly, the predictive value of iCol III for graft survival in terms of CAN was significant (Cox p = 0.088). Group 1 progressor patients (n = 10) were all males (p = 0.038) and received their kidneys from donors who died from CVAs in 90% of cases (p = 0.011). They had, compared to non-progressors, a lower cyclosporin A level (p = 0.047), a higher incidence of AR episodes (80% versus 54%), a higher serum creatinine at 10 days post-Tx (p = 0.005), a higher proteinuria (2.07 ± 3.89 g/l vs 0.96 ± 0.97 g/l, p = 0.041) and a higher serum triglyceride (2.48 ± 1.37 mmol/l vs 1.69 ± 0.81 mmol/l, p = 0.039) level. 8% of Group 1 patients had DGF compared to 30% in Group 2 (p = 0.023). Of note, the modal category of cytotoxic: helper T lymphocytes ratio was greater than 1 in Group 1 (2 : 1) patients and not in Group 2 (1 : 1). Conclusion: Implantation histology, and in particular iCol III, is a predictor of early IF in a subgroup of patients with DGF and AR. Additional risk factors include hypertension, proteinuria and hypertriglyceridemia especially in patients receiving kidneys from older donors who died of CVAs.
Originals
Type 2 angiotensin II receptor expression in human renal allografts: an association with chronic allograft nephropathy
B.N. Becker, L.M. Jacobson, D.A. Hullett, N.A. Radke, T.D. Oberley, P.C. Brazy and A.D. Kirk
B.N. Becker, L.M. Jacobson, D.A. Hullett, N.A. Radke, T.D. Oberley, P.C. Brazy and A.D. Kirk
1Department of Medicine, Division of Nephrology, 2Department of Surgery, Division of Transplantation, 3Department of Pathology and Laboratory Medicine, University of Wisconsin, Department of Veterans Affairs Hospital, Madison, WI, and 4NIDDK-Navy Transplantation and Autoimmunity Branch, National Naval Medical Center, Bethesda, MD, USA Aims: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type 1 angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. Materials and methods: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA, matrix-modulating genes and histologic evidence of chronic rejection were assessed. Results: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (rs) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-b (TGF-b) (rs 0.59; p = 0.044), matrix metalloproteinase-1 (MMP-1) (rs 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (rs 0.74; p = 0.001) and TIMP-3 (rs 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). Conclusions: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.
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