Renal hypodysplasia (RHD) is characterized by a reduced nephron number, small kidney size, and disorganized renal tissue. A hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes that are involved in early kidney organogenesis. Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome). For estimation of the prevalence of these events, an unselected cohort of 99 unrelated patients with RHD that was associated with chronic renal insufficiency were screened for mutations in TCF2, PAX2, EYA1, SIX1, and SALL1. Mutations or variants in the genes of interest were detected in 17 (17%) unrelated families: One mutation, two variants, and four deletions of TCF2 in eight unrelated patients; four different PAX2 mutations in six families; one EYA1 mutation and one deletion in two patients with branchio-oto-renal syndrome; and one SALL1 mutation in a patient with isolated RHD. Of a total of 27 patients with renal cysts, six (22%) carried a mutation in TCF2. It is interesting that a SIX1 sequence variant was identified in two siblings with renal-coloboma syndrome as a result of a PAX2 mutation, suggesting an oligogenic inheritance. Careful clinical reevaluation that focused on discrete extrarenal symptoms and thorough family analysis revealed syndrome-specific features in nine of the 17 patients. In conclusion, 15% of patients with RHD show mutations in TCF2 or PAX2, whereas abnormalities in EYA1, SALL1, and SIX1 are less frequent.
While the anti-hypertensive and renoprotective potency of angiotensin-converting enzyme (ACE) inhibitors is well established in adults with hypertension and/or chronic renal failure, little experience exists in pediatric chronic kidney disease. As part of a prospective assessment of the renoprotective efficacy of ACE inhibition and intensified blood pressure (BP) control, 397 children (ages 3 to 18 years) with chronic renal failure [CKD stage II to IV] and elevated or high-normal BP received ramipril (6 mg/m2) following a 6-month run-in period including a two-month washout of any previous ACE inhibitors. Drug efficacy was assessed by two monthly office BP and proteinuria assessments, and by ambulatory BP monitoring at start and after 6 months of treatment. In the 352 pediatric patients completing six months of treatment, 24-hour mean arterial pressure (MAP) decreased by a mean of 11.5 mm Hg (-2.2 SDS) in initially hyper-tensive subjects, but only by 4.4 mm Hg (-0.8 SDS) in patients with initially normal BP. A linear correlation was found between MAP at baseline and the change of MAP during treatment. The anti-hypertensive response was independent of changes in concomitant anti-hypertensive medication or underlying renal disease. BP was reduced with equal efficacy during day- and nighttime. Urinary protein excretion was reduced by 50% on average, with similar relative efficacy in patients with hypo/dysplastic nephropathies and glomerulopathies. The magnitude of proteinuria reduction depended on baseline proteinuria, and was correlated with the antihypertensive efficacy of the drug. The incidence of rapid rises in serum creatinine and progression to end-stage CRF during treatment did not differ from the pretreatment observation period. Mean serum potassium increased by 0.3mmol/L. Ramipril was discontinued in three patients due to symptomatic hypotension or hyperkalemia. Hemoglobin levels decreased by 0.6 g/dL in the first two treatment months and remained stable thereafter. CONCLUSION: Ramipril appears to be an effective and safe antihypertensive and antiproteinuric agent in children with CRF-associated hypertension. The BP lowering and antiproteinuric effects are greatest in severely hypertensive and proteinuric children. The dissemination of these data intends to encourage antihypertensive and antiproteinuric treatment by ACE inhibition in all children with chronic renal failure for prevention of renal disease progression.
In order to maximize transparency, document the evolution of the project and facilitate information exchange, a study website was created (http://www.escape-trial.org) on a secure SSL server containing a public and a password-protected domain. On the public domain, information regarding the objectives and design of each work package as well as regarding the partners involved are available. The restricted-access domain contains proprietary information for the group members, informing them about the progress and results of the study. This approach guaranteed a continuous communication flow within the group. Furthermore a file server for exchange of large files was been installed. In addition, the possibility for online discussion for more than two participants (online conferences) was created. Any arising problems, relevant decisions or new results were made public to all participants in a News section. All progress reports were posted on the website. Online data entry via the Website of the group was offered. Patient-related laboratory results were also transmitted electronically and stored in the central database on a Server at Heidelberg University Computing Facilities. The Coordinating Office redistributes, in regular intervals or by demand as appropriate, patient-related data and laboratory specimens to the work package partners for analysis. Data were transferred via email or file server.
Increased left ventricular (LV) mass in children with chronic renal insufficiency (CRI) might be adaptive to sustain myocardial performance in the presence of increased loading conditions. We hypothesized that in CRI children LV systolic function is impaired despite increased LV mass. Standard echocardiograms were obtained in 130 children aged 3-18 years (59% boys) with stage II-IV chronic kidney disease and in 130 healthy children of similar age, gender distribution and body build. Systolic function was assessed by measuring fractional shortening at the endocardial (eS) and midwall (mS) levels and computation of end-systolic stress (myocardial after-load). Results. The CRI patients exhibited a 6% lower eS and 10% lower mS than normals, in the presence of significantly elevated blood pressure, increased LV mass and more concentric LV geometry. Whereas the decreased eS was entirely explained by augmented end-systolic stress, mS remained reduced after correction for myocardial after-load. The prevalence of subclinical systolic dysfunction as defined by impaired mS was more than 5-fold higher in CRI patients compared to normal controls. Systolic dysfunction was most common (48%) in patients with concentric hypertrophy and associated with lower hemoglobin levels. In conclusion, CRI in children is associated with impaired intrinsic LV contractility, which parallels increased LV mass.
Urinary excretion of endothelin-1, transforming growth factor ß1and vascular endothelial growth factor (165) in pediatric chronic kidney disease
The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGFß-1 and VEGF165 was evaluated in 303 children with CKD stage II-IV and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N=183), obstructive uropathies (N=47), glomerulopathies (N=34), nephronophthisis (N=19), and polycystic kidney disease (N=20). The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls. The excretion of ET-1 and TGFß1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGFß1 and VEGF excretion rates were weakly inversely correlated with age and renal function. VEGF and TGFß1 excretion rates were positively correlated both in patients and controls. In conclusion, children with CKD exhibit significantly elevated urinary excretion of ET-1, TGFß1 and VEGF165 in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGFß1 and VEGF165 excretion shown both in patients and healthy controls indicates an interdependent nature of their generation.
Dissociation of anti-proteinuric and anti-hypertensive efficacy of long-term ACE inhibition in children with chronic renal failure
The ESCAPE Trial evaluates the renoprotective efficacy of constant ACE-inhibition with ramipril (6mg/m²/d) in children with chronic renal failure. In 100 children receiving ramipril for 3 years 24h-mean arterial pressure was persistently reduced from +1.2 to -0.1, -0.1, -0.3, and -0.2 SDS after 0.5, 1, 2, and 3 years, respectively. The mean protein/creatinine-ratio decreased from 1.0mg/mg at baseline to 0.46 after 6 months treatment (p<0.0001). However, proteinuria increased again during ongoing treatment and reached the baseline level at the end of the third treatment year (mean 0.87mg/mg). The initial drop in proteinuria was positively correlated with baseline proteinuria and negatively with GFR. The rebound of proteinuria was independent of age, GFR, blood pressure and rate of CRF progression prior to and under ramipril treatment. Out of 78 patients with an initial proteinuria reduction, a rebound during ongoing treatment by >50% of the initial drop was observed only in 1 of 9 with glomerular but in 35/69 with hypo-dysplastic disorders. In the actuarial survival analysis of the total ESCAPE cohort (400 pts), ongoing proteinuria (>150mg/m²/d) during ramipril treatment was associated with a significantly poorer renal survival. In summary, a partial loss of the antiproteinuric efficacy is observed during long-term ACE inhibition in many children with chronic renal failure. This effect is dissociated from a persistently good blood pressure control, and may compromise the long-term nephroprotective action of ACE inhibition. Concepts of intensified ACE inhibition or additional blockade of the angiotensin-receptor should be evaluated in these patients.
Renal hypodysplasia, characterized by a decrease in nephron number, small overall kidney size, and mal-developed renal tissue, is a leading cause of chronic renal failure in young children. Familial clustering and renal hypodysplasia phenotypes observed in transgenic animal models suggest a genetic contribution. Uroplakin IIIa (encoded by UPIIIA) is an integral membrane protein present in urothelial plaques, and the murine UPIIIa knockout is associated with urothelial anomalies and vesicoureteral reflux. De novo UPIIIA mutations recently were identified in 4 of 17 patients with severe bilateral renal adysplasia. To evaluate the overall role of UPIIIA in human renal hypodysplasia pathogenesis, we performed UPIIIA mutation analysis in a cohort of 170 pediatric patients affected by severe unilateral or bilateral renal hypodysplasia. Eighty-one patients were affected by bilateral nonobstructive renal hypodysplasia; of these, 61 were without vesicoureteral reflux. Eighty-four patients presented with unilateral nonobstructive renal hypodysplasia, including 24 patients with unilateral multicystic dysplastic kidneys. Family history was positive in 11%. Mutation analysis showed 2 heterozygous mutations not observed in 200 race-matched control chromosomes. In only 1 family was distribution of the UPIIIA mutation consistent with a disease-causing effect. This de novo missense mutation (Gly202Asp) was identified in a patient with unilateral multicystic dysplastic kidneys. The second (intronically located) mutation appeared unlikely to be disease causing because it did not segregate with an obvious disease phenotype in the affected family. In conclusion, our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals.
Gene mutations in SIX2 and BMP4 are associated with anomalous development of the kidney in humans and zebrafish
Renal hypodyslasia (RHD) is characterized by a reduced kidney size and/or mal-development of the renal tissue following disturbed organogenesis. In a subset of affected individuals human gene mutations have been identified. Here, we report on the first mutations in human BMP4 and SIX2 identified in patients with RHD, among these three different mutations in BMP4 in five unrelated RHD patients (Ser91Cys, Thr116Ser, Asn150Lys) and three different mutations in SIX2 also in five unrelated patients (Leu43Phe, Pro241Leu, Asp276Asn). Over-expression assays in zebrafish demonstrate that these mutations affect the function of Bmp4 and Six2 in vivo: over-expression of Six2 and Bmp4 results in dorsalization and ventralization, respectively, suggesting opposing roles for mesendoderm formation. These effects are diminished after over-expression of mutant constructs expressing the human mutations identified. Morpholino knockdown of bmp4 and six2.1 reveals specific roles of these genes for pronephric development, affecting the expression of wilms tumor-1 (wt1) and glomerular development. These studies implicate Six2 and Bmp4 as important players in the development of the renal system, and suggest that defects in these proteins could affect kidney development at multiple stages leading to the congenital defects observed in RHD patients.
Ultradian but not circadian blood pressure rhythms correlate with renal dysfunction in children with chronic renal failure
Whereas the diurnal fall of BP (dipping) is an important prognostic marker in patients with chronic renal failure (CRF), the integrity of physiologic ultradian (i.e., shorter than 24 h) cardiovascular rhythms in patients with CRF is unknown. Also, the relationship between conventional dipping analysis and Fourier spectral rhythm analysis has not been examined in renal hypertension. The prevalence and dimensions of the circadian and three ultradian (12, 8, and 6 h) cardiovascular rhythms were studied by ambulatory BP monitoring in 214 children (aged 3 to 18 yr) with CRF (stage 2 to 4 chronic kidney disease) and no antihypertensive treatment compared with 938 healthy control subjects, and the relationship of rhythm characteristics to conventional dipping parameters, renal function, proteinuria, and serum electrolytes was assessed. The CRF cohort exhibited significantly reduced amplitudes of the circadian and all ultradian cardiovascular rhythms studied. Moreover, all BP and most heart rate rhythms showed significantly delayed acrophases (time of peak). Whereas conventional BP dipping parameters (day/night difference, day/night ratio) and the 24-h BP amplitude were independent of renal function, the 8-h BP amplitude was positively correlated with GFR (r = 0.3, P = 0.01) and inversely correlated with the urinary protein/creatinine ratio, and the 6-h BP amplitude was inversely correlated with proteinuria. Children who displayed 24- or 12-h cardiovascular rhythms had significantly lower serum calcium levels than children without these rhythms. In summary, children with CRF display not only blunted circadian but also blunted ultradian cardiovascular rhythms. Ultradian but not circadian rhythms or conventional dipping parameters are quantitatively associated with renal function and proteinuria.
Ambulatory blood pressure monitoring (ABPM) provides superior information for diagnosis and treatment of pediatric hypertension, but for reasons of practicality, clinic blood pressure measurements (CBP) are still the primary diagnostic tool. Regular home blood pressure measurements (HBP) may be an alternative to ABPM, but this technique awaits validation in practice. Therefore, we analysed the concordance of ABPM, CBP and HBP in 118 pediatric patients (3-19 y) with chronic renal failure. HBP readings (10.5 +/- 5.4 per patient) were averaged for one week around the day of ABPM and CBP. Mean arterial pressure (MAP) measured by HBP was significantly lower than both CBP and daytime ABPM. HBP detected hypertensive patients with greater specificity, but lower sensitivity than CBP. The fraction of patients rated. The 95% limits of agreement with ABPM were narrower for HBP (-23 to10mm Hg) than for CBP (-30 to 21mm Hg). CBP, but not HBP measurements, were less precise in the upper BP range. The accuracy of HBP measurements did not change with use over a six months time period. In conclusion, HBP was superior to CBP in predicting ABPM, but neither CBP nor HBP detected hypertension with enough sensitivity or specificity to replace ABPM. The greater specificity of HBP compared with CBP makes it a more suitable tool for diagnosis, rather than screening, of hypertension in children.
Altered morphological and mechanical properties of large arteries in children with chronic renal failureand after renal transplantation
Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD, 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.
Left ventricular hypertrophy (LVH) is the most important independent marker of cardiovascular risk in adults with chronic kidney disease. Cardiovascular morbidity seems increased even in children with chronic renal insufficiency (CRI), but the age and stage of CRI when cardiac alterations become manifest are unknown. For assessing the prevalence and factors associated with abnormal LV geometry in children with CRI, echocardiograms, ambulatory BP monitoring, and biochemical profiles were obtained in 156 children aged 3 to 18 yr with stages 2 through 4 chronic kidney disease and compared with echocardiograms obtained in 133 healthy children of comparable age and gender. LV mass was indexed to height2.7. Concentric LV remodelling was observed in 10.2%, concentric LVH in 12.1%, and eccentric LVH in 21% of patients. LVH was more common in boys. Probability of LVH independently increased with male gender and standardized body mass index. Low hemoglobin, low GFR, young age, and high body mass index were independent correlates of LV mass index. LV concentricity (relative wall thickness) was positively associated with serum albumin. Probability of abnormal LV geometry increased with C-reactive protein >10mg/dl. In conclusion, substantial cardiac remodelling of both concentric and eccentric type is present at young age and early stages of CRI in children. Prevalence of LVH is related to male gender, anemia, and ponderosity but not to BP. Additional effects of volume status and inflammation on cardiac geometry are also evident.
Normative values for intima-media-thickness and distensibility of large arteries in healthy adolescents
Sonographic evaluation of arterial wall morphology and elasticity is increasingly accepted as a non-invasive tool in cardiovascular assessment. Several studies suggest that intima-media thickness (IMT) and arterial elasticity indices may sensitively reflect different vasculopathic processes in children. However, normative values and the impact of adolescent growth are largely unknown. METHODS: We assessed the IMT of the common carotid (cIMT) and femoral arteries (fIMT), carotid elasticity indices and interacting anthropometric factors in 247 healthy subjects aged 10-20 years. cIMT, fIMT, incremental elastic modulus (Einc) and circumferential wall stress (CWS) were positively, and distensibility coefficient (DC) inversely, correlated with age, height, body mass index (BMI), systolic blood pressure (BP) and brachial pulse pressure. DC and stiffness index beta, but not Einc, were significantly associated with cIMT independently of age. All vascular parameters showed non-Gaussian distributions. Excessively high IMT was associated with BMI and pulse pressure above the 90th percentile, and elevated Einc with high-normal BMI. Multivariate analysis identified independent positive effects of standardized BMI and brachial pulse pressure on normalized cIMT, negative effects of systolic BP and cIMT on DC, a positive effect of cIMT on stiffness, and positive effects of systolic BP and BMI on Einc and CWS. In conclusion, morphological and functional measures of large arteries should be normalized to take account of changes during adolescence and skewed distributions. Relative body mass, systolic blood pressure and/or pulse pressure are determinants of IMT and elasticity.
The proto-oncogene RET a member of the tyrosine-kinase receptor its ligand GDNF and the co-receptor GFR?1 play a pivotal role during early nephrogenesis and enteric nervous system development. In humans, activating RET mutations cause multiple endocrine neoplasia, whereas inactivating mutations lead to Hirschsprung disease. Although RET deficiency causes renal hypodysplasia (RHD) in a mouse model, genetic abnormalities in RET have not been characterized in human isolated renal malformations. We screened 99 children from an unselected cohort of RHD from 12 European countries for sequence variation in the genes encoding RET, GDNF and GFRalpha1. We found the RET mutation Y971F in six patients and the RET mutation S649L in one patient. These mutations reportedly predispose humans to the emergence of medullary thyroid carcinoma (MTC). None of the patients or their carrier relatives had clinical evidence of MTC at the time of the study. The Y791F mutation was found in 6 of 42 patients from Germany, Poland and Serbia but in none of the other countries. Haplotype analyses indicate that the RET Y791F mutation was inherited from a common ancestor living approximately 26 generations ago. Low penetrance of RHD was suggested by minimal or lacking renal phenotypes in most carrier relatives. We also found a GDNF mutation and a previously described EYA1 mutation in addition to the RET Y791F mutation in a patient. RHD was limited to the single- family member heterozygous for all three mutations, suggesting oligogenic disease transmission. Conclusion Our findings suggest that RET mutations predispose to the emergence of both MTC and RHD, with a low penetrance for either disorder. The RET Y791F mutation may be a common genetic abnormality underlying RHD in children of Central European ancestry that, in view of its important clinical implications, may deserve general screening in this population. The finding of mutations in different genes in the same family supports a multigenic model of inheritance for RHD.
Bone morphogenetic proteins (BMPs) are a subgroup of the TGFß superfamily involved in body patterning and morphogenesis. They regulate a variety of cellular processes in different organs,e.g. differentiation, proliferation and apoptosis. In the kidney, Bmp4 inhibits abnormal budding from the Wolffian duct by antagonizing inductive signals from the metanephric mesenchyme (MM) and promotes kidney development by stimulating the elongation of the branching ureter within the MM. The murine knock-out of Bmp4 is associated with renal agenesis, hypodysplasia or cystic dysplasia. Bmp4 is synthesized as an inactive 46.5 KDa precursor, and proBmp4 is cleaved to yield the mature active protein dimer. We report on the first human mutations identified in BMP4 (S91C, N150K, T116S) in five unrelated children with severe renal hypodysplasia (RHD). All mutations are located in the prodomain of Bmp4, a domain frequently affected by human mutations in other members of the TGFß family. All mutants are abundantly expressed and secreted by transfected COS7 and HEK293 cells. RNA analysis revealed a reduced mRNA expression of all Bmp4 mutants as compared to wild type (wt), indicating a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, non- reducing Western analysis revealed that S91C-Bmp4 forms alternative protein complexes as compared to wt-Bmp4, possibly due to extra disulfide bonds. This observation was confirmed using reducing conditions and different disulfide bond blockers. The precise molecular structure of these protein complexes remains to be identified by MALDI-TOF analysis. We postulate that abnormal Bmp4 protein-protein-interactions are involved in the pathogenesis of human RHD.
The prevalence and characteristics of physiological circadian (24-hour) and ultradian (12-, 8-, and 6-hour) rhythms of mean arterial blood pressure (BP) and heart rate (HR) were analysed by 24-hour ambulatory BP profiles from 938 healthy school children aged 5 to 18 years. Cosine harmonics were fitted by Fourier analysis, and an amplitude and acrophase (time of peak) were calculated for each rhythm. Ninety percent of children displayed circadian rhythmicity of BP, independent of age, whereas circadian HR rhythmicity decreased with puberty from 96% to 87%. Puberty had marked effects on the prevalence of ultradian rhythmicity: 12- and 6-hour rhythms increased for BP (27% to 47%; 18% to 25%) and HR (36% to 47%, 17% to 31%), whereas 8-hour BP rhythms decreased (34% to 23%). Median amplitudes were 10.1, 5.9, 5.6, and 5.2mm Hg for the 24-, 12-, 8-, and 6-hour BP rhythms, respectively, and 13.4, 7.7, 6.8, and 6.4bpm for HR. The acrophase occurred at approximately 14:00 hours, 8:00 hours, 5:30 hours, and 2:00 hours (military time) for the four BP rhythms, and at 13:30 hours, 08:30 hours, 01:50 hours, and 02:00 hours for HR. For the combined curve, the peak-trough difference was 25.9mm Hg and 35bpm for BP and HR, respectively, with the peaks occurring at 13:50 hours and 13:10 hours. There was marked association between BP and HR rhythms, both for prevalence and timing, with a median time lag of BP after HR acrophase of only 21, 16, 13, and 5 minutes for the four rhythms, respectively. Normative data for blood pressure and heart rate rhythmicity were provided to allow pediatricians and others interested in cardiovascular health to perform inter- or intraindividual comparative analyses on this subject.
This prospective, controlled study was designed to verify the hypothesis that the treatment modality significantly affects the evolution of CKD-associated arteriopathy. 56 pediatric patients (mean age 13.8 +/- 4.2 years) with chronic kidney disease (CKD) stage 3-5(CKD group) and 32 patients dialyzed at baseline (D), of whom 19 received a renal allograft (rTx) and 13 remained on D. Sonography of the common carotid artery was performed at baseline and after 12 months. Intima media thickness (IMT) and the cross-sectional areas of the vessel wall (WCSA) and lumen (LCSA) were measured and normalized to age (SD scores). At baseline IMT and WCSA were increased above normal in all patient groups, and significantly higher in D than in CKD patients. Whereas IMT increased over time in patients who remained in CKD or on D. IMT and WCSA decreased after rTx in the patients with elevated IMT at time of grafting. While IMT was independently correlated with blood pressure and serum phosphate in the CKD and D patients, only total dialysis vintage and the IMT attained at time of grafting predicted IMT one- year post-rTx. In conclusion, while vascular lesions rapidly progress in CKD and D patients, abolition of the uremic state by rTx leads to partial regression of CKD-associated arteriopathy. Cumulative dialysis duration and the degree of renal damage prevalent at time of grafting are the main determinants of persisting arteriopathy one year after rTx.