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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

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Volume 57 (2002) p. 9 - 18

Abstract

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

Prednisolone and azathioprine in membranous nephropathy: a 10-year follow-up study

D.S. Goumenos, M. Ahuja, P. Davlouros, A.M. El Nahas and C.B. Brown

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Volume 65 (2006) p. 217 - 223

Abstract

D.S. Goumenos, M. Ahuja, P. Davlouros, A.M. El Nahas and C.B. Brown

¹Nephrology, Internal Medicine, University Hospital, Patras, Greece, ²Sheffield Kidney Institute, Sheffield Teaching Hospitals, Northern General Campus, Sheffield, UK, ³Cardiology, Internal Medicine, University Hospital, Patras, Greece
Background: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although its clinical course is usually benign, some patients develop chronic renal failure. Combination of corticosteroids with cytotoxic drugs and cyclosporin have been used in the treatment of the disease. Conflicting results are reported with the use of prednisolone and azathioprine. In this study, the effect of treatment with prednisolone and azathioprine and the parameters related to a poor outcome over a follow-up period of 10 years is estimated. Methods: 50 patients were included in this study; 33 were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg body weight/day) in gradually reduced doses for 26 ± 9 months, whereas 17 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or end-stage renal failure (ESRF). The contribution of clinical and histological parameters in the clinical outcome was examined by univariate and multivariate analyses. Results: Doubling of baseline serum creatinine was observed in 20 of 50 patients (40%), 14 from treated and 6 from the untreated group (42% vs. 35%, p = NS). ESRF developed in 10 of 50 patients (20%), 7 from treated and 3 from the untreated group (21% vs. 18%, p = NS). Most patients from both groups who reached the end-points had impaired renal function at presentation and persistent nephrotic syndrome during the follow-up period. Both parameters were identified as independent risk factors related to an unfavorable clinical outcome. No difference in the remission rate of nephrotic syndrome was observed between treated and untreated patients (51% vs. 58%, p = NS). Conclusion: Treatment with prednisolone and azathioprine seems to be of no long-term benefit in ameliorating the clinical course of nephrotic patients with membranous nephropathy. Thus, other therapeutic regimens including cyclophosphamide, chlorambucil or cyclosporin should be used in nephrotic IMN patients with poor prognostic features. Correspondence to:
D.S. Goumenos, MD
Department of Internal Medicine, Nephrology
University Hospital
26 500 Patras, Greece
Email: [email protected]

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