Title: Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable kidney disease, affecting ∼1 in every 1000 subjects.1Torres V.E. Harris P.C. Pirson Y. Autosomal dominant polycystic kidney disease.Lancet. 2007; 369: 1287-1301Abstract Full Text Full Text PDF PubMed Scopus (1019) Google Scholar Most affected subjects show progressive renal function decline and need renal replacement therapy (RRT) between their 40th and 70th year of age.2Gabow P.A. Autosomal dominant polycystic kidney disease.N Engl J Med. 1993; 329: 332-342Crossref PubMed Scopus (851) Google Scholar, 3Iglesias C.G. Torres V.E. Offord K.P. et al.Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980.Am J Kidney Dis. 1983; 2: 630-639Abstract Full Text PDF PubMed Scopus (299) Google Scholar, 4Hateboer N. v Dijk M.A. Bogdanova N. et al.Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.Lancet. 1999; 353: 103-107Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar Over the past decades several treatment options have emerged to postpone the need for RRT in subjects with chronic kidney disease, such as strict blood pressure control, renin–angiotensin–aldosterone system inhibition, and low-protein diets. These treatment options have also been tested in subjects with ADPKD with disappointing results.5Schrier R. McFann K. Johnson A. et al.Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study.J Am Soc Nephrol. 2002; 13: 1733-1739Crossref PubMed Scopus (176) Google Scholar, 6van Dijk M.A. Breuning M.H. Duiser R. et al.No effect of enalapril on progression in autosomal dominant polycystic kidney disease.Nephrol Dial Transplant. 2003; 18: 2314-2320Crossref PubMed Scopus (72) Google Scholar, 7Klahr S. Breyer J.A. Beck G.J. et al.Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group.J Am Soc Nephrol. 1995; 5: 2037-2047PubMed Google Scholar However, the results obtained in ADPKD studies should be interpreted with caution, as these studies were in general insufficiently powered to reach definitive conclusions (75, 89, and 200 patients, respectively). Furthermore, the ADPKD patients who were included were often still in that phase of their disease at which renal function is relatively stable. In such patients it is difficult to study the renoprotective efficacy of interventions. Therefore, a conclusive answer to the question whether conventional renoprotective regimens are effective in ADPKD patients is still lacking. Interestingly, two observational studies have suggested that in ADPKD patients the average age at onset of end-stage renal disease (ESRD) has increased considerably during the last two decades.8Schrier R.W. McFann K.K. Johnson A.M. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease.Kidney Int. 2003; 63: 678-685Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar,9Orskov B. Romming Sorensen V. Feldt-Rasmussen B. et al.Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark.Clin J Am Soc Nephrol. 2010; 5: 2034-2039Crossref PubMed Scopus (46) Google Scholar This finding has been interpreted as that effective renoprotective therapies have emerged for ADPKD, with especially males having achieved a better prognosis. However, these observational studies were performed in relatively small patient populations (513 and 693 patients, respectively), which may have led to publication bias. It is surprising to note that the epidemiology of RRT for ADPKD has seldom been studied, especially because ADPKD is one of the most common causes of ESRD. Given these considerations we used the European Renal Association-European Dialyses and Transplant Association (ERA-EDTA) Registry data to provide the largest epidemiological data set on ADPKD yet. We used these data to study changes in the incidence rate of RRT, and the average age and treatment modality at onset of RRT. The hypothesis of this study was that, with a stable prevalence of ADPKD in the general population, changes in the incidence rate of RRT may provide indications whether renoprotective treatments have emerged for ADPKD during the last two decades. Between 1991 and 2010 a total of 314,176 patients from 12 countries started RRT; of them, 20,483 had ADPKD as the cause of kidney failure and 293,693 patients had other kidney diseases. An overall 54% of ADPKD patients and 62% of non-ADPKD patients were male. Over this time period the crude incidence rate of RRT for ADPKD increased from 6.9 to 8.4 per million population (p.m.p.). Table 1 shows the international variation in the age- and sex-adjusted RRT incidence rate of ADPKD subjects, which in the most recent period ranges from 5.3p.m.p. in Romania to 10.0p.m.p. in Belgium. Figure 1 visualizes these differences in RRT incidence rates for ADPKD geographically.Table 1Incidence rate of renal replacement therapy for ADPKD on day 1, and incidence rate of dialysis (hemodialysis and peritoneal dialysis) or kidney transplantation as the primary modality of RRT on day 91 (middle and lower panel, respectively)1991–19951996–20002001–20052006–2010ChangeaChange between 1991–1995 and 2006–2010.p.m.p.p.m.p.p.m.p.p.m.p.%All RRT Austria6.88.18.07.3+7.4 BelgiumbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.6.99.48.910.0NA Denmark7.28.08.28.1+12.5 Finland6.58.57.87.1+9.2 France9.4NA Greece6.47.48.17.6+18.8 Italy, Calabria7.69.37.4-2.7 Romania5.3NA SpainbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.9.610.49.39.2NA Sweden8.68.78.79.1+5.8 The Netherlands7.67.27.77.1-6.6 United KingdombCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.5.96.46.47.1NA All countriescAverage of countries with complete coverage during all four study periods.7.68.58.58.3+9.2Dialysis Austria6.57.57.56.50.0 BelgiumbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.6.68.68.59.2NA Denmark6.07.27.47.3+21.7 Finland6.08.47.66.9+15.0 France7.9NA Greece6.37.47.87.3+15.9 Italy, Calabria7.38.76.9-5.4 Romania5.0NA SpainbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.9.310.08.98.5NA Sweden7.57.87.57.8+4.0 The Netherlands7.36.97.26.0-17.8 United KingdombCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.5.55.95.85.9NA All countriescAverage of countries with complete coverage during all four study periods.7.28.08.07.5+4.2Kidney transplantation Austria0.20.30.30.6+200 BelgiumbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.0.30.50.20.5NA Denmark0.90.60.50.7-22.2 Finland0.40.10.20.1-75.0 France1.3NA Greece0.00.00.10.2NA Italy, Calabria0.00.00.1NA Romania0.1NA SpainbCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.0.00.30.30.5NA Sweden0.90.70.91.1+22.2 The Netherlands0.30.20.51.0+233 United KingdombCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.0.10.40.51.1NA All countriescAverage of countries with complete coverage during all four study periods.0.30.30.40.7+133Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; NA, not applicable or available (due to change in coverage over time); p.m.p., per million of the population; RRT, renal replacement therapy.Rates are standardized for age and sex to the 2005 EU27 population, and expressed per million population.a Change between 1991–1995 and 2006–2010.b Coverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.c Average of countries with complete coverage during all four study periods. Open table in a new tab Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; NA, not applicable or available (due to change in coverage over time); p.m.p., per million of the population; RRT, renal replacement therapy. Rates are standardized for age and sex to the 2005 EU27 population, and expressed per million population. Although the relative contribution of ADPKD to the total incident RRT population decreased from 7.7% in 1991–1995 to 6.1% in 2006–2010 (Supplementary Figure S1 online), the average age- and gender-adjusted incidence rate has increased by 9.2% from 7.6p.m.p. in 1991–1995 to 8.3p.m.p. in 2006–2010 (Table 1). Differences in trends were observed among countries, with the Netherlands and Italy showing a slight decrease and other countries showing an increase over time. Download .doc (.16 MB) Help with doc files Supplementary Figures Table 2 shows country-specific data and the mean age at onset of RRT for ADPKD patients for each of the four study periods. We observed an increase in the mean age at start of RRT from 56.6 to 58.0 years (P<0.001). The mean age at onset of RRT was significantly higher in women than in men at all time periods (P<0.001). From 1991 to 2010 the mean age increased on average by 1.4 years in men and by 1.5 years in women. In non-ADPKD patients, the mean age at the start of RRT increased from 57.6 to 64.7 years (P<0.001). Over time, the age-adjusted male/female ratio of RRT incidence for ADPKD has remained stable (1.19, 1.28, 1.20, and 1.20, respectively). The additional analyses of estimated glomerular filtration rate (eGFR) data collected for an earlier study showed for a subgroup of ADPKD patients that the average eGFR in ADPKD patients at onset of dialysis increased only slightly (by 0.6ml/min per 1.73m2, from 7.2 to 7.8ml/min per 1.73m2) in 2003 compared with 1999.Table 2Mean age (in years) of ADPKD and non-ADPKD patients starting renal replacement therapy, country-specific data and average (for which only countries are taken into account with complete coverage during all four study periods)1991–19951996–20002001–20052006–2010All RRT for ADPKD Austria57.459.158.659.5 BelgiumaCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.58.158.259.558.9 Denmark55.658.160.059.9 Finland54.057.357.358.3 France58.9 Greece55.156.758.158.9 Italy, Calabria61.559.860.2 Romania55.9 SpainaCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.56.857.658.057.6 Sweden58.757.960.658.2 The Netherlands56.556.256.758.4 United KingdomaCoverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.54.955.556.555.5 All countriesbAverage of countries with complete coverage during all four periods.56.657.458.258.0 Female57.158.458.758.6 Male56.156.557.757.5All RRT for non-ADPKD All countriesbAverage of countries with complete coverage during all four periods.57.660.863.564.7 Female57.961.464.162.5 Male57.360.463.164.5Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; RRT, renal replacement therapy.a Coverage of the general population by the renal registry increasing over time, see for details Supplementary Table S1 online.b Average of countries with complete coverage during all four periods. Open table in a new tab Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; RRT, renal replacement therapy. Figure 2 shows the incidence rate of RRT for ADPKD per age group for each of the four study periods. Importantly, there was no change in the incidence rate in subjects up to 50 years of age. Only the incidence rate in subjects older than 70 years of age increased. Over the four study periods the incidence rate in subjects younger than 30 years remained stable at <0.5p.m.p. (Supplementary Figure S2 online). Similarly, the incidence rates remained fairly stable or changed minimally in patients in their third to sixth decade of life: 3.0 to 3.1p.m.p., 11.9 to 12.8p.m.p., 19.0 to 18.8p.m.p., and 17.0 to 17.5p.m.p., respectively, when comparing the time periods 1991–1995 and 2006–2010. In contrast, for patients aged 70–79 and above 80 years the incidence increased from 14.3 to 17.3p.m.p. and from 3.0 to 9.2p.m.p.. In both age groups, a plateau was reached during the last study period (2006–2010) (Supplementary Figure S2 online). Figure 3 shows the association between the incidence rates of RRT for ADPKD and those for non-ADPKD patients in the time period 2006–2010. It indicates that countries with a high take-on rate for RRT in general also have a high take-on rate for ADPKD patients. In an additional analysis including only patients older than 70 years of age also a positive association was found between ADPKD and non-ADPKD patients R2=0.651, β=0.02 (95% confidence interval 0.01-0.02, P=0.002). This indicates that countries with a high take-on rate for elderly non-ADPKD patients also have a high take-on rate for elderly ADPKD patients. During the four study periods, the age- and sex-adjusted percentage of ADPKD patients who were started on RRT on hemodialysis decreased from 73.6 to 70.1% from 1991 to 2010 (Table 3), whereas peritoneal dialysis remained stable at ∼22% and transplantation increased from 3.9 to 8.1%. Figure 4 shows that ADPKD patients start RRT as often on peritoneal dialysis as do non-ADPKD patients. A clear difference is noted for kidney transplantation, which is more often the initial treatment modality in ADPKD than in non-ADPKD patients. A similar trend is observed for patients receiving kidney transplantation from either living or deceased donors (Supplementary Figure S3 online).Table 3Trends over time in treatment modality on which ADPKD patients start renal replacement therapyADPKD1991–1995 (%)1996–2000 (%)2001–2005 (%)2006–2010 (%)Change (%)aChange between 1991–1995 and 2006–2010.Hemodialysis73.677.374.270.1-4.8Peritoneal dialysis22.419.321.521.6-3.6Kidney transplant recipients3.93.44.48.1+108 Living donor1.31.72.85.6+319 Deceased donor2.41.51.52.3-1.7 Unknown donor0.20.30.10.2+8.7Non-ADPKDHemodialysis74.977.279.979.4+6.0Peritoneal dialysis22.520.517.716.7-25.8Kidney transplant recipients2.62.32.33.8+46.2 Living donor1.11.21.42.6+130 Deceased donor1.21.00.81.0-17.7 Unknown donor0.20.20.10.20.0Abbreviation: ADPKD, autosomal dominant polycystic kidney disease.For these data only countries were taken into account with complete coverage during all 4 periods.Percentages are standardized for age and sex to the 2005 EU27 population.a Change between 1991–1995 and 2006–2010. Open table in a new tab Figure 4Treatment modality at day 91 after starting renal replacement therapy comparing autosomal dominant polycystic kidney disease (ADPKD) patients with non-ADPKD patients. Patients on hemodialysis (upper panel), peritoneal dialysis (middle panel), and kidney transplant recipients (lower panel) as a percentage of the incident renal replacement therapy (RRT) population. Data are the average of the period 2006 through 2010 and adjusted for age and sex to the distribution of the EU27 population in 2005. The size of the marker denotes the size of the general population under study. AT, Austria; BE, Belgium; DK, Denmark; ES, Spain; FI, Finland; FR, France; GR, Greece; IT, Italy; NL, The Netherlands; RO, Romania; SE, Sweden; UK, United Kingdom.View Large Image Figure ViewerDownload (PPT) Abbreviation: ADPKD, autosomal dominant polycystic kidney disease. For these data only countries were taken into account with complete coverage during all 4 periods. Percentages are standardized for age and sex to the 2005 EU27 population. This study shows that the incidence rate of RRT and the age at onset of RRT for ADPKD have increased slightly. Importantly, for ADPKD patients up to 50 years of age the RRT incidence rate expressed per million of the age-related population has remained stable, whereas at older age an increase was observed. Furthermore, a positive association was found between the RRT incidence rate for ADPKD and that for non-ADPKD patients. We interpret these findings as probably being due to more number of elderly patients starting RRT, rather than that being a consequence of effective renoprotective treatments having emerged for ADPKD. Two observational studies have addressed this issue previously. Data from the University of Colorado Health Sciences Center suggested that recent ADPKD patients have a significantly slower rate of ADPKD progression.8Schrier R.W. McFann K.K. Johnson A.M. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease.Kidney Int. 2003; 63: 678-685Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar In this study the average median survival time to RRT was investigated in two cohorts of patients (i.e., 1985–1992 vs. 1992–2001). The average age at start of RRT increased substantially for both male and female patients (from 53 to 63 years and from 57 to 61 years, respectively). A Danish population study showed that the incidence rate increased from 6.45 to 7.59p.m.p. over a period of 17 years (1990–2007) and that the age at starting RRT also increased (from 55.9 to 60.6 years).9Orskov B. Romming Sorensen V. Feldt-Rasmussen B. et al.Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark.Clin J Am Soc Nephrol. 2010; 5: 2034-2039Crossref PubMed Scopus (46) Google Scholar The former study was relatively small with only 513 ADPKD patients included, and the baseline characteristics of the two studied cohorts differed, suggesting that the later cohort may have had a milder form of ADPKD. The Danish study reported country-wide data. However, given the fact that ADPKD has a population prevalence of 1:1000 and that ADPKD is a slowly progressive disease, the number of ADPKD patients who were started on RRT during the study period was still relatively low (n=693), and consequently did not allow us to reliably report RRT incidence data per age group. In line with the aforementioned literature, the present study showed that the age at onset of RRT has increased during the last decades, although it is considerably lower (from 56.6 to 58.0 years) than reported previously. Of note, a recent study from the Catalan registry that is included in the present report showed no change in age at onset of RRT.10Martinez V. Comas J. Arcos E. et al.Renal replacement therapy in ADPKD patients: a 25-year survey based on the Catalan registry.BMC Nephrol. 2013; 14: 186Crossref PubMed Scopus (23) Google Scholar Furthermore, we also observed that the age- and sex-adjusted RRT incidence rate increased for ADPKD by 9.3% during the four study periods. Importantly, we established that the incidence rate of RRT for ADPKD remained stable up to 50 years of age and increased only in subjects aged 70 years or older. The combination of an increase in the incidence rate of RRT and an increase in the age at onset of RRT may be interpreted in various ways. This combination may suggest that overall prognosis, as well as kidney prognosis, has improved in ADPKD patients. However, it may also be that, specifically, more number of elderly patients are starting RRT nowadays. If effective renoprotective treatment had emerged during the last two decades in ADPKD, it would be expected that the entire curve of the incidence rate per million of the age-related population would have shifted to the right for the most recent study periods, because renoprotective treatments would affect all age groups. However, we found no change in the incidence rate up to 50 years of age. This age group is thought to reflect the true incidence rate of kidney failure. Younger patients are less subject to variation in access and referral to RRT compared with older patients.11Stengel B. Billon S. Van Dijk P.C. et al.Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, 1990-1999.Nephrol Dial Transplant. 2003; 18: 1824-1833Crossref PubMed Scopus (219) Google Scholar Furthermore, in this age group the mortality as competing risk for initiation of RRT is low. Therefore, we derive from our data that no effective renoprotective therapies have emerged for ADPKD. This may seem to be in contrast to both aforementioned observational studies.8Schrier R.W. McFann K.K. Johnson A.M. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease.Kidney Int. 2003; 63: 678-685Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar,9Orskov B. Romming Sorensen V. Feldt-Rasmussen B. et al.Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark.Clin J Am Soc Nephrol. 2010; 5: 2034-2039Crossref PubMed Scopus (46) Google Scholar However, because of the limited size of their included populations it was not possible in these studies to investigate incidence data per age group, as in the present study. We found that the RRT incidence rate curve shifted to the right only after the age of 70 years, indicating that in this age group, and especially in the very elderly (≥80 years), RRT incidence increased. This is compatible with the widespread clinical notion that nowadays more number of elderly patients start RRT because of changes in RRT take-on policies and due to a reduction in the competing risk of mortality. Our interpretation that no effective renoprotective treatment has emerged for ADPKD is further supported by the positive association between the incidence rate of RRT for ADPKD and that for non-ADPKD. Countries with a high overall RRT take-on rate also have a higher RRT take-on rate for ADPKD. Of note, recent studies suggest that vasopressin V2 receptor antagonists and somatostatin analogs ameliorate the rate of decline in kidney function in ADPKD patients.12Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1014) Google Scholar,13Caroli A. Perico N. Perna A. et al.Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.Lancet. 2013; 382: 1485-1495Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar However, these treatments are not available for clinical use in ADPKD patients yet. Theoretically, there may be several potential explanations as to why the incidence rate of RRT has not changed in younger ADPKD patients, despite the renoprotection that may have been obtained in this age group. First, it could be that survival in young ADPKD patients before onset of RRT has improved. Clinical experience and scant literature indicate, however, that mortality in ADPKD patients before the age of 55 years is very low,12Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1014) Google Scholar,14Torres V.E. King B.F. Chapman A.B. et al.Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease.Clin J Am Soc Nephrol. 2007; 2: 112-120Crossref PubMed Scopus (124) Google Scholar, 15Walz G. Budde K. Mannaa M. et al.Everolimus in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 830-840Crossref PubMed Scopus (454) Google Scholar, 16Serra A.L. Poster D. Kistler A.D. et al.Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 820-829Crossref PubMed Scopus (447) Google Scholar making it unlikely that this would have biased our results. Second, the average eGFR at which RRT is initiated may have increased, leading to an earlier start of RRT. The analysis of eGFR data at the start of RRT derived from a previous ERA-EDTA registry study showed that in ADPKD patients the average eGFR at the onset of dialysis was higher in 2003 than in 1999.17Stel V.S. Tomson C. Ansell D. et al.Level of renal function in patients starting dialysis: an ERA-EDTA Registry study.Nephrol Dial Transplant. 2010; 25: 3315-3325Crossref PubMed Scopus (37) Google Scholar However, this difference was small (0.6ml/min per 1.73m2), whereas the rate of eGFR loss in ADPKD is between 3 and 6ml/min per 1.73m2 per year.6van Dijk M.A. Breuning M.H. Duiser R. et al.No effect of enalapril on progression in autosomal dominant polycystic kidney disease.Nephrol Dial Transplant. 2003; 18: 2314-2320Crossref PubMed Scopus (72) Google Scholar,7Klahr S. Breyer J.A. Beck G.J. et al.Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group.J Am Soc Nephrol. 1995; 5: 2037-2047PubMed Google Scholar,15Walz G. Budde K. Mannaa M. et al.Everolimus in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 830-840Crossref PubMed Scopus (454) Google Scholar,16Serra A.L. Poster D. Kistler A.D. et al.Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 820-829Crossref PubMed Scopus (447) Google Scholar These data indicate that a higher eGFR at the start of RRT translates into an earlier start of RRT at a maximum of 0.5 year, which would not substantially influence our data in Figure 2. Third, there may be relatively more ADPKD subjects in the general population at present. Unfortunately, reliable data on ADPKD population prevalence over time are unavailable. As ADPKD is a hereditary disease and as most affected subjects are aware from their relatives that it is associated with an unfavorable prognosis, it may be expected that, given the widespread availability of contraceptives nowadays, family size has remained the same or has become smaller rather than increased. Therefore, we consider it unlikely that an increase in ADPKD population prevalence would have biased our interpretation of the