Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations
2012; Elsevier BV; Volume: 81; Issue: 8 Linguagem: Inglês
10.1038/ki.2011.452
ISSN1523-1755
AutoresJohanna Temme, Frederik Peters, Katharina Lange, Yves Pirson, Laurence Heidet, Roser Torrá, Jean‐Pierre Grünfeld, Manfred Weber, Christoph Licht, G. A. Müller, Oliver Groß,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoWe studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan–Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed ‘familial benign hematuria.’ Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension. We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan–Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed ‘familial benign hematuria.’ Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension. Alport syndrome is a hereditary basement membrane disorder due to mutations within type IV collagen genes.1.Alport A.C. Hereditary familial congenital haemorrhagic nephritis.BMJ. 1927; 1: 504-506Crossref PubMed Scopus (497) Google Scholar,2Hudson B. Tryggvason K. Sundaramoorthy M. et al.Alport's syndrome, Goodpasture's syndrome, and type IV collagen.N Engl J Med. 2003; 348: 25Google Scholar Mutations of the COL4A5 gene encoding the α5-chain of type IV collagen lead to X-linked Alport syndrome (XLAS), whereas mutations of the COL4A4/COL4A3 genes encoding the α3/α4 (IV) chains cause the autosomal recessive form (ARAS) of the disease.3.Flinter F.A. Cameron J.S. Chantler C. et al.Genetics of classic Alport's syndrome.Lancet. 1988; ii: 1005-1007Abstract Scopus (181) Google Scholar,4.Gross O. Weber M. From the molecular genetics of Alport's syndrome to principles of organo-protection in chronic renal diseases.Med Klin. 2005; 100: 826-831Crossref Scopus (3) Google Scholar Men with XLAS and patients of both genders with homozygous ARAS mutations represent the completely developed pattern of the disease with end-stage renal failure during adolescence or early adulthood, including hearing loss and ocular lesions in most of them.5Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males.J Am Soc Nephrol. 2000; 11: 649-657Crossref PubMed Google Scholar In these patients, the course of Alport syndrome has been well studied, including their genotype–phenotype correlations5Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males.J Am Soc Nephrol. 2000; 11: 649-657Crossref PubMed Google Scholar, 6Gross O. Netzer K.-O. Lambrecht R. et al.Meta-analysis of genotype–phenotype correlation in X-linked Alport syndrome: impact on genetic counseling.Nephrol Dial Transpl. 2002; 17: 1218-1227Crossref PubMed Scopus (193) Google Scholar, 7.Bekheirnia M.R. Reed B. Gregory M.C. et al.Genotype-phenotype correlation in X-linked Alport syndrome.J Am Soc Nephrol. 2010; 21: 876-883Crossref PubMed Scopus (162) Google Scholar and the beneficial effect of timely nephroprotective therapy.8.Gross O. Kashtan C. Treatment of Alport syndrome: beyond animal models.Kidney Int. 2009; 76: 599-603Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Analysis of heterozygous XLAS carriers in the ‘European Community Alport Syndrome Concerted Action’9.Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a ‘European Community Alport Syndrome Concerted Action’ Study.J Am Soc Nephrol. 2003; 14: 2603-2610Crossref PubMed Scopus (314) Google Scholar showed a large variability of the clinical course. Hematuria was found in 96% and proteinuria in 75% of the patients; 18% reached end-stage renal failure (59% of them before the age of 40 years). These data showed that the diagnosis of heterozygous COL4A5 mutations is not equivalent to a benign course of disease. The reasons for the large inter- and intrafamilial variability in clinical manifestations in those female patients are only partially known; probably X-inactivation has a pivotal role.10.Kashtan C.E. Alport syndrome and the X chromosome: implications of a diagnosis of Alport syndrome in females.Nephrol Dial Transplant. 2007; 22: 1499-1505Crossref PubMed Scopus (41) Google Scholar Heterozygous COL4A3/COL4A4 mutations result in the phenotype ‘familial benign hematuria’ or ‘thin basement membrane nephropathy’ (TBMN).11.Buzza M. Wilson D. Savige J. Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome.Kidney Int. 2001; 59: 1670-1676Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 12.Gross O. Netzer K.O. Lambrecht R. et al.Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome.Nephrol Dial Transplant. 2003; 18: 1122-1127Crossref PubMed Scopus (43) Google Scholar, 13Heidet L. Arrondel C. Forestier L. et al.Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome.J Am Soc Nephrol. 2001; 12: 97-106PubMed Google Scholar Affected subjects typically present with hematuria. Histologically, TBMN is characterized by a uniformly thinned glomerular basement membrane. Having been regarded as ‘benign’ familial hematuria for a long time, these patients might have an increased risk to develop severe renal impairment14.Nieuwhof C.M. de Heer F. de Leeuw P. et al.Thin GBM nephropathy: premature glomerular obsolescence is associated with hypertension and late onset renal failure.Kidney Int. 1997; 51: 1596-1601Abstract Full Text PDF PubMed Scopus (107) Google Scholar, 15.van Paassen P. Breda Vriesman P.J. van Rie H. et al.Signs and symptoms of thin basement membrane nephropathy: a prospective regional study on primary glomerular disease: the Limburg Renal Registry.Kidney Int. 2004; 66: 909-913Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 16.Dische F.E. Weston M.J. Parsons V. Abnormally thin glomerular basement membranes associated with hematuria, proteinuria or renal failure in adults.Am J Nephrol. 1985; 5: 103-109Crossref PubMed Scopus (105) Google Scholar, 17.Tiebosch A.T. Frederik P.M. Breda Vriesman P.J. et al.Thin-basement-membrane nephropathy in adults with persistent hematuria.N Engl J Med. 1989; 320: 14-18Crossref PubMed Scopus (165) Google Scholar, 18.Savige J. Rana K. Tonna S. et al.Thin basement membrane nephropathy.Kidney Int. 2003; 64: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 19.Gregory M.C. The clinical features of thin basement membrane nephropathy.Semin Nephrol. 2005; 25: 140-145Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar—comparable to the findings in female XLAS carriers (see above). TBMN is not a rare disease, as at least 1% of the population is affected;12.Gross O. Netzer K.O. Lambrecht R. et al.Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome.Nephrol Dial Transplant. 2003; 18: 1122-1127Crossref PubMed Scopus (43) Google Scholar,18.Savige J. Rana K. Tonna S. et al.Thin basement membrane nephropathy.Kidney Int. 2003; 64: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar in a series of 76 renal transplant biopsies, even 5.2% of the kidneys presented a thinned glomerular basement membrane.16.Dische F.E. Weston M.J. Parsons V. Abnormally thin glomerular basement membranes associated with hematuria, proteinuria or renal failure in adults.Am J Nephrol. 1985; 5: 103-109Crossref PubMed Scopus (105) Google Scholar For the first time, the present study compares the risk of renal impairment, end-stage renal disease, and premature death between heterozygous carriers of XLAS and ARAS mutations. In addition, the nephroprotective effect of renin–angiotensin–aldosterone system (RAAS) blockade in patients with heterozygous Alport mutations is evaluated. Founded in 2006, the European Alport Registry retraces clinical and therapeutic data on several decades in three generations of Alport families across Europe. Patient information, study protocol, questionnaire (see Supplementary Material online), consent form (in English, French, Spanish, and German), data collection, anonymization, and storage conform with good clinical practice guidelines, and were approved by the Ethics Committee (AZ 10/11/06; authorization of French data by the Commission Nationale de l’Informatique et des Libertés #908249). Analysis included 234 patients, 29 of them with ARAS mutations (14 men and 15 women); the mean age of all patients was 35.1±19.5 years, and the mean age at start of RAAS blockade therapy was 28.2±15.7 years. In all, 3 (10.3%) of these ARAS patients are currently under renal replacement therapy, 5 (17.2%; mean age 45 years) show an impaired creatinine clearance, 10 (34.5%; mean age 35 years) present with proteinuria, and 10 (34.5%; mean age 15 years) with microalbuminuria. In all, 189 patients had a XLAS mode of inheritance (16 patients with unknown mode, but biopsy-proven thin basement membrane disease). Of them, 29 (15.4%) are under renal replacement therapy, 27 (14.3%; mean age 48 years) have an impaired creatinine clearance, 63 (33.0%; mean age 29 years) present with proteinuria, and 35 (18.5%; mean age 24 years) with microalbuminuria (Figure 1 and Table 1).Table 1Renal impairment in heterozygous ARAS and XLAS carriers: total numbers, proportions, and mean agesAutosomal recessiveX-linkedRenal replacement therapy3/29 (10.3%)29/188 (15.4%)Impaired creatinine clearance5/29 (17.2%; 44.8 years)28/188 (14.9%; 48.2 years)Proteinuria10/29 (34.5%; 34.7 years)62/188 (33.0%; 28.5 years)Microalbuminuria10/29 (34.5%; 15.4 years)35/188 (18.6%; 24.3 years)Abbreviations: ARAS, autosomal recessive form; XLAS, X-linked Alport syndrome. Open table in a new tab Abbreviations: ARAS, autosomal recessive form; XLAS, X-linked Alport syndrome. A total of 41 patients (34 XLAS carriers) reached end-stage renal failure (median age at onset of renal replacement therapy (RRT) 49 years, 95% confidence interval (CI) 59–75 years; 1 male, 40 females; Figure 2). Of them, 6 had a nephroprotective RAAS blockade before start of RRT; 11 received a kidney transplant, and 3 of these kidney transplants failed (after 16, 15, and 7.5 years). There are no significant differences in age at onset of RRT between the groups. Life expectancy was evaluated in 213 carriers; 21 of these patients were on RRT (transplanted or dialysis). A total of seven patients died (two transplanted patients, four under dialysis, and one under dialysis, who had undergone transplantation earlier). As this is a relatively small number of events, the median time of survival could not be determined. Therefore, survival is described by the 75% quartile, which is calculated to be 70 (95% CI 67–undetermined years). ‘Time on dialysis’ was found to affect life expectancy; therefore, end-stage renal disease in Alport carriers seems to increase the risk of premature death (Figure 3; Supplementary Material 1, Supplementary Material 2 online). Download .doc (.04 MB) Help with doc files Supplementary Material 1 Download .doc (.03 MB) Help with doc files Supplementary Material 2 A total of 111 patients (47%) received nephroprotective therapy (mean age at onset of therapy 28 years): 109 were treated with angiotensin converting enzyme inhibitors (ACEis), 34 with angiotensin receptor blockers, and 21 with a combination of ACEis and angiotensin receptor blockers (Figures 4 and 5). The number of ARAS heterozygotes on therapy was too low for separate analysis in Figure 4. Average time on therapy was 5.8 years (s.d.=3.8 years, range 1–21 years). Among the patients under therapy, 53 (47.4%) currently have proteinuria, 27 (24.3%) have an impaired creatinine clearance, and 17 (15.3%) have microalbuminuria. Six patients (5.4%) patients reached end-stage renal failure despite RAAS blockade. In contrast, 124 patients did not receive any nephroprotective therapy, 7 of them (5.7%) showed an impaired creatinine clearance, 20 (18.0%) had proteinuria and 37 (33.3%) had microalbuminuria; 28 untreated subjects (25.2%) reached end-stage renal failure (Figure 4). Age at onset of RRT in patients having received a nephroprotective therapy before end-stage renal failure differs from untreated patients: onset of RRT occurred significantly later in carriers who were treated with RAAS blockade (Figure 5; P<0.0001). Whether this association is causal requires further study. Subgroup analysis revealed a significant effect of RAAS blockade in delaying onset of RRT in XLAS carriers (P 300mg/day), and ‘age at death’. Owing to the genetic defect in Alport carriers at birth, life expectancy was defined as life span from birth to death. Impaired creatinine clearance was defined as 300mg protein per day, and microalbuminuria as 30–300mg protein per day in a 24-h urine collection. The study explored the treatment effects of ACEis and angiotensin receptor blockers; the control intervention was with out therapy. The most commonly used ACEis were Ramipril (0.025–0.1mg/kg body weight) and Enalapril (0.125–1.0mg/kg body weight). Distributions of continuous variables are summarized by means, whereas frequencies and percentages are given for categorical (including binary) variables. The efficacy end points ‘age at onset of RRT’ and ‘age at death’ are censored in some patients, as not all patients included in the analyses have started RRT (or died). Therefore, appropriate statistical methods for censored time-to-event data were used, including the Kaplan–Meier estimator and the log-rank test.24.Bland J.M. Altman D.G. Statistics note: the logrank test.BMJ. 2004; 328: 1073Crossref PubMed Scopus (429) Google Scholar Median event times are reported with 95% CIs, which are based on log–log transformed CIs of the event probabilities. If the CIs of the event probabilities are too wide across all observed times because of the small sample size, the confidence limits for the median cannot be determined. All analyses are of an exploratory nature and therefore no correction for multiple testing was applied. All reported P-values are two-sided, and those smaller than 0.05 are referred to as statistically significant. All inferential analyses were carried out using SAS version 9.2. We thank the more than 500 patients and relatives, 310 participating centers and the French, Spanish, Belgian, Swiss, and German patients advocacy groups (AIRG and Alport Selbsthilfe e.V.) for their contributions. We thank Til Faßheber, MD, for his expert help in classifying patients, and cand. meds. Sebastian Brinkmann, Caroline Lehmann, Susanne Stietz, Christopher Bach, Catharina Wüst, and Angela Coordes for their help in collecting the data. Mutation analysis of most patients was performed by Corinne Antignac (French patients) and Mato Nagel (German patients). The European Alport Registry is supported by the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques (AIRG) and the KfH Foundation Preventive Medicine (Fritz-Scheler Stipendium of the German Society of Nephrology). Parts of the registry data were made public in abstract form at the annual meetings of the German and American Societies of Nephrology, the European Renal Association, the German Society of Pediatric Nephrology and the International Pediatric Nephrology Association. Supplementary Material S1. RAAS inhibition delays onset of end-stage renal failure in XLAS and ARAS heterozygotes. Supplementary Material S2. Impact of ‘time on dialysis’ on ‘life-expectancy/survival’ in Alport carriers. Supplementary Material S3. Letter from the Ethics Committee of the Medical Faculty of the Georg August University Gottingen. Supplementary Material S4. Questionnaire: Alport syndrome. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki Download .pdf (.15 MB) Help with pdf files Supplementary Material 3 Download .pdf (.12 MB) Help with pdf files Supplementary Material 4
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