QJM Advance Access originally published online on May 6, 2005
QJM 2005 98(6):443-449; doi:10.1093/qjmed/hci072
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Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units
From the 1Glasgow Royal Infirmary, Glasgow, 2Southmead Hospital, Bristol, 3Leicester General Hospital, Leicester, 4St Helier Hospital, Carshalton, 5Robertson Centre for Biostatistics, University of Glasgow, Glasgow, and 6Queen Elizabeth Hospital, Birmingham, UK
Address correspondence to Dr C.M. Stirling, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF. e-mail: cathstirling{at}hotmail.com
Received 19 November 2004 and in revised form 11 March 2005
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Background: Focal segmental glomerulosclerosis (FSGS) is the least studied of the causes of idiopathic nephrotic syndrome, and there are few specific guidelines for treatment.
Aim: To review data from five UK renal units to investigate whether adult patients with FSGS were treated uniformly, and to examine the effect of treatment on proteinuria and survival.
Design: Retrospective record review.
Methods: We examined electronic records of patients with idiopathic FSGS for information on baseline clinical parameters, treatment regimens and outcomes.
Results: Of 136 patients with primary FSGS and nephrotic range proteinuria, 76 (56%) were treated with prednisolone and of this group, 59% were treated with additional immunosuppression. Among the treated patients, the total remission rate (complete and partial) was 67%, and one hospital achieved a remission rate of 80%. Treated patients had a significantly higher remission rate than those who were not treated. Remission was associated with a 5-year survival off dialysis of 94%, compared with 53% if remission was not achieved. Baseline serum creatinine and remission were independently associated with survival off dialysis in a multivariate Cox proportional hazards model.
Discussion: Patients with primary FSGS and nephrotic range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated. Remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis. Patients who do not achieve remission have a poor prognosis. Further clarification of optimal treatment regimens requires additional, prospective studies.
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Introduction |
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Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome, accounting for between 10% and 35% of adult cases.1,2 Primary FSGS is particularly difficult to study, because there are no clear-cut diagnostic criteria, and it is likely to represent more than one disease. Historically, the prognosis of untreated nephrotic patients is poor, with 50% developing end-stage renal failure within 8 years, and spontaneous remissions are rare.3,4 Treatment with prednisolone for 4–8 weeks has a marginal effect on outcomes, but in more recent studies, high-dose prednisolone for longer periods of 4–5 months improved response rates from 15% to 50%.5,6 However, there have been no randomized controlled trials (RCTs) of corticosteroids in FSGS. The benefit of adding cytotoxic agents, such as cyclophosphamide, remains controversial. Some RCTs have demonstrated a beneficial effect of cyclosporin for 6 months in patients with FSGS who were resistant to an 8-week course of prednisolone,7,8 but there is little other evidence to guide clinicians in the detailed treatment of patients with FSGS. The published evidence to date consists mainly of small case-controlled series from single centres, but there have been no large European studies reported.
The aims of this study were: (i) to establish whether patients with FSGS from five different UK renal units shared similar characteristics and were treated uniformly; (ii) to examine the effect of treatment on proteinuria and survival.
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Methods |
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Five UK centres in Birmingham, Leicester, London, Glasgow and Bristol participated in the study. Predetermined clinical data were extracted locally from electronic patient records, biopsy reports were reviewed and the final dataset was analysed by a single observer centrally.
Inclusion criteria for patients were: (i) nephrotic syndrome (>3 g/day proteinuria or serum albumin <30 g/l) or nephrotic range proteinuria (>3 g/day proteinuria); (ii) FSGS proven by renal biopsy; and (iii) absence of known causes of secondary FSGS (other glomerulonephritis, infection (HIV, Hep B, Hep C), morbid obesity, reflux nephropathy). There were no other exclusion criteria. The period of recruitment varied between centres according to availability of data, but covered a period between 1975 and 1999. The majority of patients included in the study (61%) were diagnosed after 1990.
Histopathology
The histological diagnosis was taken from pathology reports in the electronic patient records, and was not formally re-examined by a histopathologist. Pathological criteria were: (i) focal segmental sclerotic lesions in more than one glomerulus on light microscopy; (ii) absence of immunoglobulin or complement deposits in glomeruli by immunofluorescence or immunoperoxidase staining, other than IgM or C3 in sclerotic lesions; and (iii) when electron microscopy (EM) available, absence of electron-dense deposits. EM was performed in >80% of biopsies, except those from Unit 3, where it was unavailable. Patients were excluded if light microscopy showed the glomerular tip lesion without other features of FSGS.9
Clinical features
The following were analysed: (i) findings at presentation (severity of proteinuria, serum albumin, serum creatinine and blood pressure); (ii) treatment (treated patients were defined as those who received corticosteroids, cyclophosphamide, cyclosporine or other immunosuppressive or cytotoxic agents; initial dose and duration of these treatments was recorded) and (iii) response to treatment (complete remission was defined as a reduction in proteinuria to <0.2 g/day, partial remission as a reduction in proteinuria to between 0.2 and 2 g/day). Time to remission was calculated from the date of first treatment to the date of remission. The final status of the patient was also recorded (alive with independent renal function, end-stage renal disease, dead).
Statistical analysis
Statistical analyses were performed using SAS for Windows (version 8.2). Baseline statistics are reported as means (SD) or medians (interquartile range, IQR) for continuous variables and number (%) for categorical variables. Continuous baseline measurements across hospitals were compared using analysis of variance (ANOVA), or Kruskal-Wallis test for skewed measurements. For pairwise comparisons, ANOVA tests or Wilcoxon Sum Rank tests were used as appropriate, and significance was taken at p<0.005 (i.e. adjustment for multiple testing). The difference between treated and untreated patients was assessed using the two-sample t-test or Wilcoxon rank sum test, as appropriate. In all cases, categorical variables were compared using the 
2 test (or Fisher's Exact test if expected counts less than 5). Adjusted p values for the difference between treated and untreated patients are also reported, and were calculated from multivariate logistic regression analysis, including baseline variables indicated in results table. Remission status was compared in a similar fashion. Time to end-stage renal failure (ESRF) or death was analysed using the log-rank test and Cox proportional hazard models. Both univariate and multivariate hazard ratios (95%CIs) and associated p values are reported for each of the baseline predictors.
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Results |
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Patient characteristics
We identified 136 patients who met the inclusion criteria from the five units. There were 86 males and 50 females, and mean age was 44 years (range 14–83 years). Table 1 shows patient characteristics at the time of biopsy in the five centres. Patients from unit 5 had significantly lower mean serum albumin at biopsy than those from units 1, 2 and 4 (all p < 0.005).
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Analysis of immunosuppression
Seventy-six patients were treated (56%). This group had evidence of more severe disease, as judged by significantly higher levels of proteinuria and lower serum albumin at presentation than untreated patients, and they were also younger (Table 2). The serum albumin and age remained statistically significant after adjustment for other patient characteristics at time of biopsy. Year of diagnosis did not influence treatment. All 76 patients were treated with prednisolone. Unit 5 treated significantly more patients than units 3 and 4 (p < 0.005, Table 1) and for a longer period (median 26 vs. 6–16 months, p = 0.0009, Table 3). No unit routinely prescribed a prolonged course of high-dose prednisolone as part of a protocol (defined as >40 mg prednisolone for >3 months). The steroid protocol in unit 5 prescribed 60 mg of oral prednisolone daily as a starting dose. This dose was then gradually reduced to 30 mg daily after 9 weeks, and to 10 mg daily by 22 weeks.
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There was variation between the five renal units in the use of additional immunosuppressive drugs. Of the treated group, 31 (41%) received prednisolone alone. Twenty-five (33%) were given cyclophosphamide, 26 (34%) cyclosporin and 20 (26%) azathioprine in addition to the corticosteroids. These agents were often used as ‘add on’ therapy in patients who had not responded to steroids alone, and some patients received more than one of these agents.
Analysis of outcomes
The overall remission rate (complete and partial) in the treated group was 67%, range 40–80% (Table 4). Unit 5 achieved the highest remission rate (80%), despite having a patient population with poorer prognostic factors, but this did not achieve statistical significance (p = 0.086, Table 4). Fourteen of the untreated patients (23%) had a spontaneous remission. Patients who were treated were more likely to achieve remission than those who were not (p < 0.000,1 2 test). This association remained statistically significant after adjustment for other patient characteristics (p = 0.0003). There was some evidence that hospital was also associated with remission (p = 0.016, 2 test), although after adjustment for treatment status and patient characteristics this was no longer significant (p = 0.52). We did not have full data on dates of remission, and therefore were unable to analyse factors associated with time from biopsy to remission.
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The number of patients reaching the endpoints of end-stage renal failure (ESRF) or death was also analysed. Survival off dialysis for all patients was 73% at 5 years and 55% at 10 years. Achievement of remission was an important predictor of outcome, with a 5-year survival off dialysis of 94% for patients entering remission, compared with 53% if remission was not achieved (Figure 1). Univariate analysis of risk factors associated with the outcomes ESRF or death showed serum creatinine at baseline and remission to be the only significant variables (Table 5). Patients with a higher serum creatinine at baseline were more likely to develop ESRF or die (HR 1.11, 95%CI 1.07–1.14, p < 0.0001) and patients in remission were less likely (HR 0.09, 95%CI 0.03–0.24, p < 0.0001). Both serum creatinine and remission remained statistically significant in the multivariate analysis. Treatment was not significantly associated with outcome univariately or in the full multivariate model, but because treatment was associated with remission, remission was removed from the multivariate model. As a result, treatment became significant, with a decreased risk of ESRF or death (HR 0.27, 95%CI 0.10–0.70, p = 0.0076, Table 5).
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The use of cyclophosphamide and other immunosuppressive agents differed from unit to unit, and we were unable to analyse the influence of these drugs from the data available.
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Discussion |
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We examined treatment regimens and outcomes of patients with FSGS, hoping to identify clinically important principles to guide management of this disease. Previous work has established prednisolone as the cornerstone of treatment, but it is not clear who should receive it, or for how long. In a review of FSGS in 1994, the results of patients treated after 1980 appeared to be much better than those before that date,3 attributed to more prolonged courses of prednisolone lasting 5–8 months compared with 2 months in the earlier period. Subsequent reports have supported this conclusion, but the optimum dose and duration of prednisolone required remains controversial. Ponticelli et al. obtained remission in 15% of patients treated for less than 16 weeks and 61% of those treated for longer.6 Alexopoulos obtained a 64% remission rate in patients treated for more than 39 weeks.10 Most reports have found prednisolone to be effective in two-thirds of patients who receive it, but it is not clear whether those who do not respond have a different disease or simply require more prednisolone.
The prognosis of untreated FSGS with nephrotic syndrome is poor, and spontaneous remissions are rare (4–6% in American studies and 16% in a European study).4,7,8 We report a spontaneous remission rate of 23%. The higher rate in Europe may reflect different disease aetiology, but tighter blood pressure control or increased use of ACE inhibitors may also contribute. Historically, approximately 50% of untreated patients died or were on dialysis within 8 years.4 This is similar to our group who did not achieve remission, in whom only 53% survived off dialysis for 5 years. For the whole group, 5- and 10-year survival rates off dialysis were 72% and 55%, and the overall remission rate was 67% with treatment. In our study, treatment was associated with remission, and remission was predictive of improved long-term outcome. This is similar to reports from other groups.11,12 Further evidence to support the use of corticosteroids in this condition comes from our finding that treatment was associated with a higher percentage of complete remissions compared to partial remissions, and the unit that treated the most patients for the longest duration had the highest remission rate (80%, unit 5).
The results achieved in unit 5, the best reported in the literature, support the hypothesis that most patients with FSGS will respond if enough treatment is given. However, despite the evidence outlined above, there was a marked variation between the units in the number of patients who were treated and in the duration of treatment. In total, 60 patients (44%) were not given prednisolone. These patients had less severe disease as demonstrated by a higher serum albumin and lower level of proteinuria compared with treated patients. The year of diagnosis did not influence the decision to treat with prednisolone. It is not clear from our data why some patients were not treated. One possibility is that they had more co-morbidity and that there was a fear of potential toxicity of corticosteroids in this group. The untreated patients were significantly older, but we do not have data on other indices of co-morbidity. However, the untreated group had a higher mortality, with nine patients dead at follow-up compared with no deaths in the treated group, possibly as a consequence of remaining nephrotic for a prolonged period. The benefits of corticosteroids may therefore outweigh the risk of potential side-effects. A recent review of FSGS concluded that all adult-onset patients with FSGS should be treated with corticosteroids.13
The role of cytotoxic therapy in the treatment of FSGS is more difficult to clarify. Reviews have suggested that cyclophosphamide and similar agents may induce remission in only an extra 10% of those who do not respond to prednisolone and are, therefore, of limited value.3,14 Some research suggests that a remission induced by prednisolone and cyclophosphamide lasts longer than one induced by prednisolone alone.6 Cyclosporin is the only agent to have been tested in randomized controlled trials of adults with FSGS.7,8,15 Two of the studies randomized adult patients who had failed to respond to a short course of prednisolone and may not therefore be truly steroid-resistant. Response rates varied from 57% to 70%, and renal function was protected in the short term, but the definition of remission was less stringent than used in this study, and relapse rates were high. In our study, 33% of patients were given cyclophosphamide, 34% cyclosporin and 26% azathioprine. Unit 2 used these agents most frequently, but there is no evidence that their patients had a better outcome. As the protocols for the use of these agents were often reserved for those who failed to respond to prednisolone alone, it is difficult to draw any firm conclusions about their use from this study.
This study has a number of limitations. The data were collected retrospectively over a long period from five centres and our findings may have been influenced by a number of unmeasured confounding variables. We were unable to analyse factors associated with time to remission—something that would be useful to investigate in future studies of this condition. Nonetheless, because we operated few exclusion criteria and collected data from renal units in different parts of the UK, we think it likely that our results reflect the general clinical experience of FSGS.
Conclusion
The results from this large case series show that patients with FSGS have different clinical characteristics, which may reflect the diversity of this disease. Patients were treated with a number of drug regimens, because we lack conclusive evidence about the best treatment in this condition. Patients treated with corticosteroids were more likely to achieve remission, and those who achieved remission had improved survival off dialysis. However, only 56% of patients were treated. Untreated patients had a poor prognosis unless they remitted spontaneously. It is not clear why more patients were not treated, and perhaps this requires further study. The main conclusion of this study is that all adult patients with primary FSGS and nephrotic range proteinuria should be treated with a prolonged course of corticosteroids. The role of cyclosporin and other cytotoxics could not be clarified in this report, but these agents may have a role in patients who fail to respond to prednisolone or as steroid-sparing agents in those who do respond. Further clarification of treatment needs additional prospective trials.
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Acknowledgments |
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We would like to thank the clinicians in the five renal units for allowing us to analyse data from their patients, and those who helped in the collection of the data, particularly Maria Langdon in Southmead Hospital Bristol.
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References |
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