Renal pathology in idiopathic membranous nephropathy: A new perspective
2006; Elsevier BV; Volume: 69; Issue: 9 Linguagem: Inglês
10.1038/sj.ki.5000289
ISSN1523-1755
AutoresS. Troyanov, L. Roasio, M. Pandes, A.M. Herzenberg, Daniel Cattran,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoHistology findings in idiopathic membranous nephropathy (MGN) have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. Renal biopsies of 389 adult MGN patients were evaluated semiquantitatively for interstitial fibrosis, tubular atrophy, vascular sclerosis, focal and segmental glomerulosclerosis lesions (FSGS), complement deposition, and stage and synchrony of deposits by electron microscopy (EM). Associations were tested between these findings and the rate of renal function decline (slope), renal survival, remission in proteinuria, and response to immunosuppression. Patients with a greater degree of tubulo-interstitial disease, vascular sclerosis, and secondary FSGS were older, had a higher mean arterial pressure, and a lower creatinine clearance at presentation. Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulo-interstitial and vascular lesions did not preclude a remission in proteinuria in those who received immunosuppressive therapy. Neither stage nor synchronicity of EM deposits nor the amount of complement deposition predicted renal survival but the latter did correlate with progression rate. In MGN, certain histologic changes are associated with renal survival outcome. However, the indicators of chronic injury are associated with age, blood pressure, and creatinine clearance at presentation and not with rate of disease progression or initial proteinuria. Histology findings in idiopathic membranous nephropathy (MGN) have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. Renal biopsies of 389 adult MGN patients were evaluated semiquantitatively for interstitial fibrosis, tubular atrophy, vascular sclerosis, focal and segmental glomerulosclerosis lesions (FSGS), complement deposition, and stage and synchrony of deposits by electron microscopy (EM). Associations were tested between these findings and the rate of renal function decline (slope), renal survival, remission in proteinuria, and response to immunosuppression. Patients with a greater degree of tubulo-interstitial disease, vascular sclerosis, and secondary FSGS were older, had a higher mean arterial pressure, and a lower creatinine clearance at presentation. Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulo-interstitial and vascular lesions did not preclude a remission in proteinuria in those who received immunosuppressive therapy. Neither stage nor synchronicity of EM deposits nor the amount of complement deposition predicted renal survival but the latter did correlate with progression rate. In MGN, certain histologic changes are associated with renal survival outcome. However, the indicators of chronic injury are associated with age, blood pressure, and creatinine clearance at presentation and not with rate of disease progression or initial proteinuria. Idiopathic membranous nephropathy (MGN) is the second most common cause of end-stage renal disease in the primary glomerulonephritis group in adults.1Maisonneuve P. Agodoa L. Gellert R. et al.Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.Am J Kidney Dis. 2000; 35: 157-165Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar The literature has consistently reported that the long-term outcome is quite variable and that reliable early predictors are still needed to ensure that potent immunosuppressive treatment targets patients that are at the greatest risk of progression.2Honkanen E. Survival in idiopathic membranous glomerulonephritis.Clin Nephrol. 1986; 25: 122-128PubMed Google Scholar, 3Noel L.H. Zanetti M. Droz D. Barbanel C. Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 4Zucchelli P. Ponticelli C. Cagnoli L. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar, 5MacTier R. Boulton Jones J.M. Payton C.D. McLay A. The natural history of membranous nephropathy in the West of Scotland.Q J Med. 1986; 60: 793-802PubMed Google Scholar, 6Wehrmann M. Bohle A. Bogenschutz O. et al.Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.Clin Nephrol. 1989; 31: 67-76PubMed Google Scholar, 7Davison A.M. Cameron J.S. Kerr D.N. et al.The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults.Clin Nephrol. 1984; 22: 61-67PubMed Google Scholar, 8Murphy B.F. Fairley K.F. Kincaid-Smith P.S. Idiopathic membranous glomerulonephritis: long-term follow-up in 139 cases.Clin Nephrol. 1988; 30: 175-181PubMed Google Scholar, 9Marx B.E. Marx M. Prediction in idiopathic membranous nephropathy.Kidney Int. 1999; 56: 666-673Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The level of renal function, degree of hypertension, and severity of proteinuria are the most common and routinely measured clinical predictors. Certain standard histologic features on renal biopsy have also long been associated with a poor outcome, particularly the severity of tubulo-interstitial damage and vascular sclerosis.3Noel L.H. Zanetti M. Droz D. Barbanel C. Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 4Zucchelli P. Ponticelli C. Cagnoli L. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar, 6Wehrmann M. Bohle A. Bogenschutz O. et al.Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.Clin Nephrol. 1989; 31: 67-76PubMed Google Scholar, 9Marx B.E. Marx M. Prediction in idiopathic membranous nephropathy.Kidney Int. 1999; 56: 666-673Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 10Ramzy M.H. Cameron J.S. Turner D.R. et al.The long-term outcome of idiopathic membranous nephropathy.Clin Nephrol. 1981; 16: 13-19PubMed Google Scholar, 11Gluck M.C. Gallo G. Lowenstein J. Baldwin D.S. Membranous glomerulonephritis. Evolution of clinical and pathologic features.Ann Intern Med. 1973; 78: 1-12Crossref PubMed Scopus (122) Google Scholar, 12Tornroth T. Honkanen E. Pettersson E. The evolution of membranous glomerulonephritis reconsidered: new insights from a study on relapsing disease.Clin Nephrol. 1987; 28: 107-117PubMed Google Scholar, 13Honkanen E. Tornroth T. Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy.Nephrol Dial Transplant. 1992; 7: 35-41PubMed Google Scholar, 14Wu Q. Jinde K. Nishina M. et al.Analysis of prognostic predictors in idiopathic membranous nephropathy.Am J Kidney Dis. 2001; 37: 380-387Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 15Toth T. Takebayashi S. Factors contributing to the outcome in 100 adult patients with idiopathic membranous glomerulonephritis.Int Urol Nephrol. 1994; 26: 93-106Crossref PubMed Scopus (20) Google Scholar, 16Ponticelli C. Zucchelli P. Passerini P. et al.A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 8-13Crossref PubMed Scopus (228) Google Scholar A correlation between the amount of complement deposition on immunofluorescence and the severity of proteinuria has also been reported.17Doi T. Kanatsu K. Nagai H. et al.Demonstration of C3d deposits in membranous nephropathy.Nephron. 1984; 37: 232-235Crossref PubMed Google Scholar Most recently, the presence of the lesion of focal and segmental glomerulosclerosis and the findings of heterogeneous vs homogeneous (synchronous) morphology of the subepithelial electron-dense deposits have been linked to a poor outcome.18Dumoulin A. Hill G.S. Montseny J.J. Meyrier A. Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis.Am J Kidney Dis. 2003; 41: 38-48Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 19Wakai S. Magil A.B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis.Kidney Int. 1992; 41: 428-434Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 20Van Damme B. Tardanico R. Vanrenterghem Y. Desmet V. Adhesions, focal sclerosis, protein crescents, and capsular lesions in membranous nephropathy.J Pathol. 1990; 161: 47-56Crossref PubMed Scopus (26) Google Scholar, 21Lee H.S. Koh H.I. Nature of progressive glomerulosclerosis in human membranous nephropathy.Clin Nephrol. 1993; 39: 7-16PubMed Google Scholar, 22Yoshimoto K. Yokoyama H. Wada T. et al.Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy.Kidney Int. 2004; 65: 148-153Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Whether these histology features predict outcome independently of the clinical parameters remains unclear. We examined these histologic features and the clinical findings at the time of renal biopsy to determine their independent value in predicting outcome in terms of not only renal survival, but also the rate of progression (slope of creatinine clearance (CrCl)), remissions in proteinuria, and on response to therapy. There were 520 patients with a diagnosis of MGN with clinical information available in the Toronto Glomerulonephritis registry from 1974 to the end of March 2003. Exclusions were <12 months follow-up (94), secondary membranous (20), <age 16 years at presentation (8), and miscellaneous (9). The remaining 389 subjects’ baseline characteristics, follow-up, and outcome are summarized in Table 1. Sixty-eight percent of patients were male, the average age was 48 years, and patients were followed for a median of 60 months. Two hundred and twenty patients received immunosuppressive treatment and 50 patients reached renal failure. On average, the first clinical assessment available predated the renal biopsy by 2 months. Only 31 patients had their biopsy delayed for more than 12 months after the first assessment. At presentation, their median proteinuria was 3.2 g/day (0.6–27.0), mean arterial pressure (MAP) was 103±14 mmHg, and CrCl was 71±21 ml/min/1.73 m2.Table 1Baseline and follow-up clinical variables (n=389)At onset Age (years)48±16 Sex (% female)33 Ethnicity (%) Caucasian/African American/Asian/other70/5/4/10 MAP (mmHg)102±14 CrCl (ml/min/1.73 m2)76±29 Proteinuria (g/day)4.7 (0.3–31.3)Follow-up Duration of follow-up (months)58 (12–400) MAP (mmHg)100±9 Proteinuria (g/day)3.9 (0.3–24.2) Immunosuppression (%)56 ACEI or ARB therapy (%)37Outcomes Rate of change in renal functionaMeasured as change in the slope of CrCl (ml/min//1.73 m2/months).-0.31±0.68 Renal failure (%)14ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CrCl: creatinine clearance; MAP: mean arterial pressure.Results are expressed as mean (±s.d.) or median (range).a Measured as change in the slope of CrCl (ml/min//1.73 m2/months). Open table in a new tab ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CrCl: creatinine clearance; MAP: mean arterial pressure. Results are expressed as mean (±s.d.) or median (range). Histology findings are summarized in Table 2. Interstitial fibrosis and tubular atrophy scores were almost identical and hence these two features were scored as a single category and assigned the highest of the two individual scores. Twenty-five percent of biopsies showed focal and segmental glomerulosclerosis lesions (FSGS) lesions. On EM, 11, 32, 22, and 35% of biopsies showed stage 1, 2, 3, and 4, respectively, with 48% showing a homogeneous and 52% showing a heterogeneous pattern.Table 2Histology findingsScore01+2+3+Tubulo-interstitial diseaseaInterstitial fibrosis and tubular atrophy scores were almost identical. These two categories were combined and categorized according to the highest score. (%)3448117Vascular sclerosis (%)4629169Complement deposition (C3) (%)32b11% were scored negative and 21% were scored trace complement deposition.332213a Interstitial fibrosis and tubular atrophy scores were almost identical. These two categories were combined and categorized according to the highest score.b 11% were scored negative and 21% were scored trace complement deposition. Open table in a new tab The κ-score was excellent for FSGS superimposed on MGN and good for interstitial fibrosis and vascular disease (κ=0.86, 0.67, and 0.60, respectively). Ninety-seven percent of the interobserver error was by a single grade (i.e. 0 vs 1, 1 vs 2, or 2 vs 3). We used the score from initial biopsy report in the analyses. Vascular and tubulo-interstitial changes were strongly correlated (spearman's ρ 0.50, P<0.001). The presence of FSGS lesions also correlated with vascular sclerosis and tubulo-interstitial lesions (spearman's ρ of 0.28 and 0.36, respectively, all P 8 g/day proteinuria, 24% had ≥moderate tubulo-interstitial fibrosis and 26% had ≥moderate vascular sclerosis and this was not significantly different from those with ≤3.5 g/day at 15 and 25%, respectively (P=NS, χ2). FSGS: focal and segmental glomerulosclerosis lesions; NS: not significant. Race and proteinuria at onset were not statistically associated with histology findings. Female patients had less interstitial fibrosis and vascular sclerosis (see text). There was no statistical association between clinical variables at onset and electron microscopy stage or C3 deposition. Race and body mass index at onset were not associated with any of the light microscopic findings. The severity of lesions by light microscopy also predicted the MAP during follow-up. The MAP in those with severe tubulo-interstitial disease was 105±9 mmHg with a median of 1 antihypertensive medication (range 0–3) compared to those with a 0 grade of 96±8 mmHg with a median of 0 antihypertensive medication (range 0–2) (P<0.001, analysis of variance and Kruskal–Wallis test). The severity of lesions also had an impact on the class of antihypertensive treatment prescribed during follow-up. Patients with severe vascular or FSGS lesions were more likely to receive an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) during follow-up (46% with FSGS lesions compared to 33% without such lesions, P=0.05, χ2). The proportion of patients given dual immunosuppression within each histology group was similar. A total of 14, 16, 18, and 17% of patients with 0, 1+, 2+, and 3+ tubulo-interstitial scores were given such therapy and 16, 15, 16, and 16% of patients with 0, 1+, 2+, and 3+ vascular sclerosis scores were so treated. Similarly, 21% of patients with FSGS lesions vs 13% without these lesions were given dual therapy (P=NS, χ2). Renal survival: Tubulo-interstitial and vascular sclerosis score did predict a lower renal survival (Figures 1 and 2) with an unadjusted hazard ratio for severe tubulo-interstitial damage of 5.5 (95% confidence interval (CI): 2.4–12.8, P<0.001) and for severe vascular lesions 4.3 (95% CI: 2.0–9.6, P<0.001) in reference to normal parenchyma. This was not, however, independent of the CrCl, age, and MAP at biopsy. The hazard ratios for severe tubulo-interstitial and severe vascular lesions adjusted for these clinical variables fell to 1.3 (95% CI: 0.4–4.2, P=NS) and 1.4 (95% CI: 0.5–4.0, P=NS), respectively. The presence of the FSGS lesions produced a trend toward a lower renal survival (unadjusted hazard ratio: 1.7; 95% CI: 0.9–3.3, P=0.13) but this disappeared after adjusting for the initial CrCl (Table 2). Slope: The rate of renal function decline was not predicted by the amount of vascular or tubulo-interstitial disease or by the presence of FSGS lesions (Table 5). tr: trace; NS: not significant. Remission in proteinuria: There was no relationship seen between grade of tubulo-interstitial and vascular damage and remission in proteinuria in patients treated with dual immunosuppression, but was seen in untreated patients (Table 4). Similarly, the presence or absence of FSGS lesions made no difference in terms of response rate in treated patients (85 vs 75% respectively, P=NS), but in untreated patients, those with FSGS lesions were less likely to remit (44 vs 68%, P=0.04, χ2). No difference in time elapsed was found from biopsy to remission or from the start of the immunosuppressive treatment to remission across the spectrum of histologic changes (data not shown). MGN: membranous nephropathy. The stage and heterogeneity of deposits did not statistically correlate with any clinical variables at onset (data not shown). Patients with a homogeneous pattern were more likely to achieve a compete remission during follow-up (42% compared to 20%, P=0.01, χ2). However, this was offset by a 35% relapse rate in the homogeneous compared to 0% in those with a heterogeneous pattern. Neither stage nor pattern of deposits predicted rate of renal function decline or renal survival. Baseline clinical variables were similar among different grades of complement deposition, although proteinuria at onset tended to be higher in those with ≥1+ C3 (5.6 g/day, range 0.3–26.2 g/day) compared to <1+ C3 (4.6 g/day, range 0.7–16.9 g/day) (P=0.06, Mann–Whitney U-test). The amount of C3 deposition did correlate with a faster rate of renal function decline (≥1+ C3: -0.46±0.76 vs <1+ C3: -0.22±0.75 ml/min/month, P=0.03 (Table 5)). There was, however, no difference in renal survival by complement grade. The unadjusted hazard ratio of renal survival in those with ≥1+ C3 in reference to those with 0.1). No correlation was seen between degree of complement deposition and remissions in proteinuria or response to immunosuppressive drugs (data not shown). We reviewed our excluded patients based on 12 ml/min/1.73 m2/year). The proportion of the patients with moderate or severe tubulo-interstitial changes was 22% and those with severe vascular change was 14%, similar to our study cohort (25 and 18%, respectively). The long-term outcome in idiopathic MGN is highly variable. The strongest predictors of renal survival in MGN are the starting glomerular filtration rate and proteinuria.23Troyanov S. Wall C.A. Miller J.A. et al.Idiopathic membranous nephropathy: definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar Although many studies have previously demonstrated the importance of histology in predicting the risk of renal failure,3Noel L.H. Zanetti M. Droz D. Barbanel C. Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 4Zucchelli P. Ponticelli C. Cagnoli L. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar, 6Wehrmann M. Bohle A. Bogenschutz O. et al.Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.Clin Nephrol. 1989; 31: 67-76PubMed Google Scholar, 9Marx B.E. Marx M. Prediction in idiopathic membranous nephropathy.Kidney Int. 1999; 56: 666-673Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 10Ramzy M.H. Cameron J.S. Turner D.R. et al.The long-term outcome of idiopathic membranous nephropathy.Clin Nephrol. 1981; 16: 13-19PubMed Google Scholar, 11Gluck M.C. Gallo G. Lowenstein J. Baldwin D.S. Membranous glomerulonephritis. Evolution of clinical and pathologic features.Ann Intern Med. 1973; 78: 1-12Crossref PubMed Scopus (122) Google Scholar, 12Tornroth T. Honkanen E. Pettersson E. The evolution of membranous glomerulonephritis reconsidered: new insights from a study on relapsing disease.Clin Nephrol. 1987; 28: 107-117PubMed Google Scholar, 13Honkanen E. Tornroth T. Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy.Nephrol Dial Transplant. 1992; 7: 35-41PubMed Google Scholar, 14Wu Q. Jinde K. Nishina M. et al.Analysis of prognostic predictors in idiopathic membranous nephropathy.Am J Kidney Dis. 2001; 37: 380-387Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 15Toth T. Takebayashi S. Factors contributing to the outcome in 100 adult patients with idiopathic membranous glomerulonephritis.Int Urol Nephrol. 1994; 26: 93-106Crossref PubMed Scopus (20) Google Scholar, 16Ponticelli C. Zucchelli P. Passerini P. et al.A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 8-13Crossref PubMed Scopus (228) Google Scholar, 17Doi T. Kanatsu K. Nagai H. et al.Demonstration of C3d deposits in membranous nephropathy.Nephron. 1984; 37: 232-235Crossref PubMed Google Scholar, 18Dumoulin A. Hill G.S. Montseny J.J. Meyrier A. Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis.Am J Kidney Dis. 2003; 41: 38-48Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 19Wakai S. Magil A.B. Focal glomerulosclerosis in idiopathic membranous glomerulonephritis.Kidney Int. 1992; 41: 428-434Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 20Van Damme B. Tardanico R. Vanrenterghem Y. Desmet V. Adhesions, focal sclerosis, protein crescents, and capsular lesions in membranous nephropathy.J Pathol. 1990; 161: 47-56Crossref PubMed Scopus (26) Google Scholar, 21Lee H.S. Koh H.I. Nature of progressive glomerulosclerosis in human membranous nephropathy.Clin Nephrol. 1993; 39: 7-16PubMed Google Scholar, 22Yoshimoto K. Yokoyama H. Wada T. et al.Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy.Kidney Int. 2004; 65: 148-153Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar few have looked at its association with the rate of renal function decline or performed multivariate analysis to account for the possible association among histology, clinical, and laboratory findings at the time of biopsy. As MGN histology is usually assessed only once, and most commonly soon after the appearance of symptoms, analyzing its predictive value must also account for any subsequent intervention that could alter the natural history of the disease. The most common and accepted interventions include blood pressure control, the use of ACEi and/or ARB class drugs, and immunosuppressive treatment. We therefore included these three factors in our analyses. Immunosuppressive therapy was divided in those who received no vs dual immunosuppression because the most recent and best evidence demonstrating the efficacy of such treatment comes from this approach.24Ponticelli C. Zucchelli P. Imbasciati E. et al.Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1984; 310: 946-950Crossref PubMed Scopus (193) Google Scholar, 25Ponticelli C. Zucchelli P. Passerini P. Cesana B. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group.N Engl J Med. 1992; 327: 599-603Crossref PubMed Scopus (149) Google Scholar, 26Ponticelli C. Altieri P. Scolari F. et al.A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.J Am Soc Nephrol. 1998; 9: 444-450PubMed Google Scholar, 27Cattran D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.Kidney Int. 2001; 59: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar We have confirmed that the severity of tubulo-interstitial and vascular damage found on light microscopy does predict renal survival but, of equal or perhaps of more importance, we found that they do not predict the rate of disease progression.3Noel L.H. Zanetti M. Droz D. Barbanel C. Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients.Am J Med. 1979; 66: 82-90Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 4Zucchelli P. Ponticelli C. Cagnoli L. Passerini P. Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome.Nephrol Dial Transplant. 1987; 2: 73-78PubMed Google Scholar, 6Wehrmann M. Bohle A. Bogenschutz O. et al.Long-term prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes.Clin Nephrol. 1989; 31: 67-76PubMed Google Scholar, 9Marx B.E. Marx M. Prediction in idiopathic membranous nephropathy.Kidney Int. 1999; 56: 666-673Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 10Ramzy M.H. Cameron J.S. Turner D.R. et al.The long-term outcome of idiopathic membranous nephropathy.Clin Nephrol. 1981; 16: 13-19PubMed Google Scholar, 11Gluck M.C. Gallo G. Lowenstein J. Baldwin D.S. Membranous glomerulonephritis. Evolution of clinical and pathologic features.Ann Intern Med. 1973; 78: 1-12Crossref PubMed Scopus (122) Google Scholar, 12Tornroth T. Honkanen E. Pettersson E. The evolution of membranous glomerulonephritis reconsidered: new insights from a study on relapsing disease.Clin Nephrol. 1987; 28: 107-117PubMed Google Scholar, 13Honkanen E. Tornroth T. Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy.Nephrol Dial Transplant. 1992; 7: 35-41PubMed Google Scholar, 14Wu Q. Jinde K. Nishina M. et al.Analysis of prognostic predictors in idiopathic membranous nephropathy.Am J Kidney Dis. 2001; 37: 380-387Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 15Toth T. Takebayashi S. Factors contributing to the outcome in 100 adult patients with idiopathic membranous glomerulonephritis.Int Urol Nephrol. 1994; 26: 93-106Crossref PubMed Scopus (20) Google Scholar, 16Ponticelli C. Zucchelli P. Passerini P. et al.A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 8-13Crossref PubMed Scopus (228) Google Scholar The association between the interstitial and vascular damage and renal survival was accounted for by a lower starting CrCl and not by a more rapid deterioration in renal function (Table 5 and Figure 3). These results strengthen the results from our earlier study, which demonstrated that elderly patients were more likely to progress to renal failure because of a lower starting CrCl and not because of the severity of their disease, as they had an almost identical rate of progression as the younger cohort as measured by the slope of their CrCl.28Zent R. Nagai R. Cattran D.C. Idiopathic membranous nephropathy in the elderly: a comparative study.Am J Kidney Dis. 1997; 29: 200-206Abstract Full Text PDF PubMed Scopus (32) Google Scholar We acknowledge that the error inherent to estimations of CrCl (instead of direct measurement) may increase the standard deviations of slopes and lower our statistical power. Nevertheless, the estimates of CrCl at onset were sufficiently precise to show clinically meaningful correlation with histology. In addition, the estimates of slope have previously allowed us to clearly discriminate patients long-term outcome in those with or without a remission in proteinuria.23Troyanov S. Wall C.A. Miller J.A. et al.Idiopathic membranous nephropathy: definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar Further support for the independence of these lesions from the disease activity is the response to immunosuppression: in patients treated with dual immunosuppression, the severity of vascular and tubulo-interstitial lesions had no effect on remission rate. This indicates that remissions in proteinuria, valid surrogates of a favorable outcome,23Troyanov S. Wall C.A. Miller J.A. et al.Idiopathic membranous nephropathy: definit
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