1 Western Infirmary, Glasgow, UK, 2 University of Helsinki, Finland, 3 University of Toronto, Ontario, 4 Glasgow University, UK and 5 North Shore Hospital, Sydney, New South Wales, Australia
Corresponding and offprint requests to: Dr Colin C. Geddes, Consultant Nephrologist, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK. Email: colin.geddes.WG{at}northglasgow. scot.nhs.uk
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. The study included 711 adults with biopsy-proven IgAN from Glasgow, UK (n = 112), Helsinki, Finland (n = 204), Sydney, Australia (n = 121) and Toronto, Canada (n = 274). Data collected from time of presentation to a nephrologist were age, gender, 24-h urine protein excretion (UP0), mean arterial pressure (MAP0) and creatinine clearance (CrCl0). Outcomes were slope of creatinine clearance (CrCl) and renal survival.
Results. At presentation there was significant vari-ability in baseline clinical features with patients from Helsinki having the lowest median UP0, lowest MAP0 and highest CrCl0, all suggesting milder disease. There was significant variability in renal survival between centres with 10-year actuarial survival of 95.7, 87.0, 63.9 and 61.6% in Helsinki, Sydney, Glasgow and Toronto, respectively (P < 0.0001; log rank). Cox proportional hazards model revealed lower age0 and lower CrCl0 were significant independent predictors of reduced renal survival. In addition, patients from Helsinki and Sydney but not Glasgow had significantly longer renal survival than patients from Toronto. Median slope of CrCl varied by region from 1.24 ml/min/year in Helsinki, to 3.99 ml/min/year in Toronto (KruskalWallis H test P < 0.0001). By multivariate analysis older age0, higher CrCl0 and lower UP0 were independently associated with slower progression. Subjects from Helsinki had a significantly slower deterioration independent of the other clinical parameters at presentation. When the 269 patients presenting with CrCl0 <75 ml/min were analysed separately there was no independent centre effect.
Conclusions. The findings are consistent with the hypothesis that geographical variability in long-term outcome of IgAN is explained by lead-time bias and inclusion of milder cases in centres with apparent good outcome, but do not exclude the possibility that some of the variability is due to other factors such as genetics, diet or treatment.
Keywords: chronic renal failure; geographical variation; IgA nephropathy; lead-time bias; natural history; progression
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Several retrospective studies have used univariate and multivariate statistical methods to identify clinical factors associated with progressive renal failure in patients with IgAN [3]. All of these studies have used dichotomous end-points such as renal survival. These studies identify poor renal function, degree of proteinuria and hypertension at the time of diagnosis as being major clinical risk factors for developing progressive renal failure. The role of gender and age at time of presentation is controversial.
Comparison of data from these series from different countries suggests that geographic variability may exist in the natural history of IgAN. This variability may be due to population genetics, environmental factors or medical management. It may, however, be due to differences in data collection, surveillance and management in different countries resulting in patients with mild disease or early disease not proceeding to renal biopsy and therefore not being included in some series. Differences in survival related to the duration of disease at time of presentation rather than true variability in disease severity is called lead-time bias and has been observed in other situations [5]. Furthermore, subjects with progressive renal failure who are lost to follow up or die before requiring dialysis will not be appropriately identified as having progressive disease by an end-point such as renal survival.
The aim of the present study was to examine data from four large IgAN databases from four different countries in three continents to extend knowledge about the long-term outcome and determine if any geographic variability in outcome is independent of renal function, proteinuria and blood pressure at the time of diagnosis. Long-term outcome was analysed as the rate of deterioration in renal function as measured by the slope of creatinine clearance (slope CrCl) as well as the traditional time to renal replacement therapy. A separate analysis of patients presenting with CrCl <75 ml/min was performed. This group was selected to ensure that they all had significant renal impairment and thus reduce the issue of geographic selection bias.
![]() |
Subjects and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Exclusions were age 14 years, other conditions associated with glomerular IgA deposition (HenochSchonlein purpura, systemic lupus erythematosus, alcohol liver disease), and patients presenting with ESRF (CrCl <15 ml/min at presentation). Patients presenting with reversible acute renal failure were included but initial presenting laboratory data were defined by when CrCl reached maximum after recovery from the acute episode.
Two outcomes were analysed. The first was renal survival as assessed by the time to development of ESRF censored for lost to follow up and death due to causes other than ESRF. The second was slope of CrCl values against duration of follow up (slope CrCl). A separate post hoc analysis of patients presenting after renal impairment had developed (CrCl at presentation <75 ml/min) was also performed to examine factors affecting progression once significant disease was established.
Slope CrCl was calculated using strict methodology. CrCl was calculated either by the classic 24 h urine creatinine excretion and simultaneous serum creatinine or by the formula of Cockcroft and Gault [13] if only the serum creatinine was available. Slope CrCl was calculated from measurements of CrCl that used the same method (i.e. for each patient the slope was calculated using CrCl measured by 24 h urine collection only or by calculated CrCl only.) For each patient all of the measures of CrCl were examined to exclude measures during episodes of transient deterioration in renal function (that might occur during acute intercurrent illness) defined as 30% deterioration in CrCl that returned to baseline. The duration of follow up to calculate slope CrCl ended if the CrCl fell below 15 ml/min for more than one measure in view of the inaccuracy of CrCl as a measure of glomerular filtration rate in advanced renal failure. After excluding these measures of CrCl each patients remaining CrCl measures were examined and the following rules were adopted in regards to the patients inclusion or exclusion from the study: if follow up was >2 years and the slope of CrCl was less negative than 1.0 ml/min/year (i.e. stable renal function) then two points were sufficient to allow inclusion; if slope CrCl was more negative than 1.0 ml/min/year (i.e. progres-sive renal failure) then a minimum of three points were required to allow inclusion. In addition patients with slope CrCl >5.0 ml/min/year (i.e. CrCl improving by >5 ml/min/year during follow up) (n = 28) were excluded as it was assumed that their presentation was after a period of acute deterioration in function. Slope CrCl was then calculated using the least squares method including all valid measures of CrCl as described above.
The impact on the two outcomes of the following variables from the time of clinical presentation to a nephrologist was analysed: age (age0), gender, mean arterial blood pressure (MAP0), urine protein excretion (UP0), creatinine clearance (CrCl0), centre. For most patients time of presentation to a nephrologist was also time of renal biopsy but for some patients there was a delay between first clinical presentation and subsequent renal biopsy. It is not possible to know how long a patient may have had evidence of glomerular disease before presentation to a nephrologists and so this is referred to as time0 rather than date of onset. Some patients presented before the first description of IgAN in 1968 but had a histological diagnosis made after this. Ethnicity was not included as the vast majority of patients were white Caucasian.
Statistics
Comparison of baseline variables between centres was by ANOVA (analysis of variance) or 4 x 2 2 test. Univariate analysis of factors affecting renal survival was by univariate Cox proportional hazards model. The influence of centre on renal survival was also analysed by KaplanMeier survival and comparison was by the log rank test. Multivariate analysis of renal survival was by a multivariate Cox proportional hazards model. Using the principle that statistical overfitting is less likely if there are 10 outcome cases per independent variable it was possible to include all of the nine variables in the model [14].
Univariate analysis of factors affecting slope CrCl was by univariate linear regression and multivariate analysis was by multiple linear regression modelling. Median slope CrCl for each centre was compared by KruskalWallis H test.
Slope CrCl was calculated using Microsoft Excel (Microsoft Corporation). Statistical analysis was done using SPSS v9.0 for Windows (SPSS Inc.). For the multivariate analyses models including all of the independent variables are presented but models using stepwise selection of independent variables were also created (but not presented) to ensure the conclusions were robust.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Slope CrCl
There was significant geographical variability in rate of loss of renal function. Median slope CrCl was 1.24 ml/min/year in Helsinki, 2.95 ml/min/year in Sydney, 3.46 ml/min/year in Glasgow and 3.99 ml/min/year in Toronto (KruskalWallis H test P < 0.0001). By univariate analysis high CrCl0, low UP0 and low MAP0 were all significantly associated with less negative slope CrCl (i.e. slower rate of deterioration in renal function) (Table 3). By multivariate analysis older age0 (standardized co-efficient [ß] 0.11; P = 0.02), higher CrCl0 (ß 0.11; P = 0.03), and lower UP0 (ß 0.33; P < 0.0001) were associated with less negative slope (Table 3). In addition, subjects from Helsinki (ß 0.12; P = 0.03) but not Sydney (ß 0.08; P = 0.092) or Glasgow (ß 0.049; P = 0.3) had a significantly slower rate of deterioration independent of the other clinical parameters at presentation when Toronto was the reference centre. UP0 had the largest impact on slope CrCl.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As with all comparative studies of the outcome of chronic diseases consideration must be given to the possibility of lead-time bias and differences in case mix at presentation due to differences in referral of patients to nephrologists and diagnostic practices within each centre. In an attempt to overcome these potential biases the present study also examined slope CrCl as an outcome variables and analysed patients presenting with CrCl <75 ml/min separately. Unlike time to ESRF, slope CrCl will not be influenced by when the patient presented in the course of the disease if the disease progressed at a uniform rate. There are several drawbacks with using slope CrCl in retrospective studies but these were addressed by using strict methodology as described.
The observation that CrCl0 was a significant independent predictor of subsequent slope CrCl is expected because many subjects with normal CrCl0 will never progress to renal failure. However, CrCl0 remained an independent predictor of subsequent slope CrCl even when subjects with established renal impairment (CrCl0 <75 ml/min) were analysed separately, implying that progression of renal failure was ever accelerating rather than truly linear. This contrasts with most studies examining progression of renal disease that tend to report a linear progression. Post-hoc analysis of data from the MDRD study (Modification of Diet and Renal Disease) [15] and the REIN (Ramipril Efficacy in Nephropathy) study [16] that both examined progression of renal failure in patients with proteinuric non-diabetic nephropathies, found that initial GFR was not an independent predictor of subsequent slope GFR in multivariate analysis, although there was a trend towards a steeper rate of decline in GFR in patients with lower initial GFR in the MDRD study. Fellin et al. [17] reported 32 patients with IgAN and renal failure and found that the pattern of progression did not consistently fit with a linear, quadratic or logarithmic function. There is a widely held view that progressive renal failure in glomerular disease, regardless of the initial aetiology, involves a continuous process of nephron loss result-ing in glomerular hyperfiltration in remaining nephrons causing further nephron loss and further glomerular hyperfiltration in remaining nephrons [18]. An accelerated rather than a linear decline in renal function is consistent with this hypothesis since the rate of loss of nephrons would be expected to occur at an ever-increasing rate under these conditions.
Despite the suggestion that the progression of renal failure was more rapid at lower levels of initial renal function in the present study, the analysis of slope CrCl and renal survival still provides insight into the progression of IgAN. Subjects from Helsinki and Sydney had longer renal survival and a flatter slope CrCl than subjects from Glasgow and Toronto (i.e. slower deterioration in renal function). After controlling for clinical variables at the time of presentation subjects from Helsinki and Sydney still had significantly longer renal survival but only subjects from Helsinki still had a flatter slope CrCl. Greater renal function at presentation and advancing age were associated with longer renal survival and slower slope CrCl while increasing proteinuria was associated with shorter renal survival and faster slope CrCl.
More than one explanation of these findings is possible. One possibility is that the differences between centres are explained entirely on the basis of lead-time bias, i.e. the natural history in all centres is similar but the disease is detected at different times in its course. Figure 2 depicts three hypothetical patients from three different countries that have an identical clinical course and demonstrates the potential of lead-time bias. This hypothetical clinical course consists of an early period of 5 years where renal function remains normal (CrCl 110 ml/min) followed by a period of accelerated decrease in CrCl over the next 7 years. Patient A lives in a country with a screening programme and the presence of the disease is detected very early in its course. Renal survival is 12.5 years, CrCl0 is 110 ml/min and slope CrCl is 6.17 ml/min/year. Patient B lives in a country where patients found to have proteinuria on routine testing are referred to nephrologists when renal function is still normal. Renal survival is 7.5 years, CrCl0 is 110 ml/min and slope CrCl is 12.3 ml/min/year. Patient C lives in a country where patients are only referred to a nephrologist if there is impaired renal function. Renal survival is 2.5 years, CrCl0 is 75.6 ml/min and slope CrCl is 26.9 ml/min/year. The model incorporates the observation that high CrCl0 is associated with less negative slope CrCl even in patients presenting with impaired renal function by depicting progressive renal failure as an accelerating process as discussed above. Comparison of these three patients using data from the time of presentation would falsely suggest that Patient A is from a country with longer renal survival and slower (less negative) slope CrCl independent of CrCl0 and that higher CrCl0 is associated with slower subsequent slope CrCl. The model has been created to illustrate the potential for lead-time bias and the numbers are arbitrary.
|
Lead-time bias is unlikely to be the only explanation for the geographical variability demonstrated in this study because the mean age at presentation was only 24 years older in the patients from Toronto and Glasgow compared with Helsinki and Sydney. The fact that the proportions of patients presenting with CrCl >75 ml/min and UP <0.5 g/day were higher in Helsinki and Sydney than in Glasgow and Toronto suggests that patients with mild disease were included in the first two centres that would not have presented to the second two centres. Many of the patients in the Helsinki cohort were referred from large army, employment and driving licence screening programmes that exist in Finland and the centre has a liberal biopsy practice in subjects with evidence of glomerular disease. The biopsy practice in Sydney was similar while in contrast patients in Toronto and Glasgow were unlikely to proceed to renal biopsy unless there was heavy proteinuria (>1 g/24 h) or renal failure. The patients presented over a large time period (19591997). The time periods were largest in Sydney and Toronto but the median year of presentation was similar between centres. To determine if time of presentation might have introduced bias the multivariate analyses were repeated with presentation after 1985 as an independent dichotomous variable and time of presentation had no significant influence (results not presented).
The findings of our study are therefore consistent with the hypothesis that the variation in the rate of progression of renal disease is mainly explained by variability at presentation in both duration (lead-time bias) and severity of disease in different countries. However, the data do not exclude the possibility that true geographic variability exists. There are several possible explanations for true geographical differences in the natural history of IgAN. The first is genetic variations between the populations that result in different outcomes of IgAN. The previous observation that polymorphisms of the ACE gene and the angiotensinogen gene appear to influence the development of progressive renal failure in IgAN lends support to this hypothesis [7,19]. Further genetic studies of the cohort in this report are on-going. Environmental factors, including dietary differences between countries may also explain differences in the outcome of IgAN. This possibility is supported by clinical trials of fish oils in IgAN that suggest that variability in the intake of omega 3 fatty acids may slow the progression of IgAN [20]. The observation that blood pressure reduction and treatment with ACE inhibiting drugs slow the progression of renal failure in IgAN suggests that differences in the medical management during the follow up of patients with IgAN may explain differences in long-term outcome between countries. Detailed comparison of the degree of blood pressure control and use of ACE inhibiting drugs would have been interesting but was not available for this cohort of patients. In all four centres, however clinical management over the time period of study was similar. ACEI were increasingly used to manage hypertension in the late 1980s and 1990s and immunosuppression and use of fish oils were not routine practice. The median year of presentation in each centre was similar and therefore similar therapeutic options for blood pressure control are likely to have been available. Recent evidence suggests smoking may adversely affect the outcome of IgAN [21]. Detailed information regarding smoking was not collected in the four centres. Histological features such as tubulo-interstitial disease might have provided interesting information to determine the role of delayed presentation to nephrologists in the observed variability but histological scoring was not available.
The role of gender in IgAN is not clear from previous published evidence. This study strongly suggests that the outcome for males and females is the same because there were no differences in renal survival or slope CrCl between males and females although hormonal status and age by gender could not be specifically assessed. There is a higher male:female ratio for patients diagnosed with IgAN in Glasgow than in other centres in this study and previous published reports. It is not clear if this is because of a true difference in incidence of disease or differences in the rate of referral of patients to nephrologists. The only way to answer this question is to introduce a systematic urinary screening programme and at present none exists in the UK.
The role of age on long-term renal survival is also unclear from previously published studies. In the present study by univariate analysis there is a significant association between advancing age and the risk of developing ESRF. Multivariate analysis however demonstrated an independent protective effect of advancing age on both the risk of developing ESRF and slope CrCl and this is consistent with data from Radford et al. [22]. Closer scrutiny of the data provides an explanation for this paradox. There is a significant inverse correlation between advancing age and CrCl0 (P = 0.01; two-tailed Pearson test); i.e. older patients are more likely to have impaired renal function at presentation and, therefore, likely to have shorter renal survival. However, in patients with impaired renal function (CrCl0 < 75 ml/min), advanc-ing age is associated with less negative slope CrCl (slower rate of deterioration). Thus, after controlling for CrCl0, age is associated with longer renal survival. In other words if two patients have the same CrCl at presentation the older patient will have slower deterioration in function and longer time to ESRF. The reason for the adverse effect of young age on progression of IgAN is not clear and deserves further study.
Increased blood pressure at presentation has an adverse impact on both renal survival and slope CrCl by univariate analysis but not by multivariate analysis. This is likely to be because patients with raised blood pressure at presentation are also likely to have raised UP0 and lower CrCl0 and these last two variables are strong predictors of reduced renal survival and faster (more negative) slope CrCl. It is known that blood pressure reduction during follow up slows progression of renal disease but assessing blood pressure control retrospectively is difficult and was not addressed in this study.
![]() |
Conclusion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Acknowledgments |
---|
Conflict of interest statement. None declared.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|