Do C1q or IgM nephropathies predict disease severity in children with minimal change nephrotic syndrome?

BACKGROUND: It has been suggested that C1q and immunoglobulin M (IgM) nephropathy are variants of minimal change nephrotic syndrome (MCNS). Many researchers believe that these two conditions signify a worse prognosis for children with MCNS in comparison with immunofluorescence (IF)-negative MCNS. The aim of our study was to determine the prognostic significance of C1q nephropathy and IgM nephropathy in children with MCNS. METHODS: Fifty-five children with MCNS who had been biopsied over the course of 24 years at our institution were retrospectively categorized into three groups on the basis of IF microscopy findings: IF-negative MCNS (29/55 patients), MCNS with IgM nephropathy (19/55 patients), and MCNS with C1q nephropathy (7/55 patients). Clinical characteristics at disease presentation, clinical course, and renal outcome were compared between groups during the median follow-up period of 16.9 years (minimum 1.0, maximum 31.1 years). RESULTS: No statistically significant differences in clinical characteristics at disease presentation, clinical course, and renal outcome were found. Children with IgM nephropathy, C1q nephropathy, and IF-negative MCNS were clinically indistinguishable. CONCLUSIONS: We concluded that C1q or IgM nephropathy variants do not seem to signify a worse prognosis in children with MCNS in comparison with IF-negative MCNS.

Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux.

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.

Ultrasound detection of vesicoureteral reflux in children.

PURPOSE: We present different ultrasound techniques to detect vesicoureteral reflux in children with special emphasis on voiding urosonography. MATERIALS AND METHODS: Urinary tract infection is a common problem in children that may be related to vesicoureteral reflux. Currently there is no consensus on investigations in children after the first urinary tract infection. The least invasive imaging with the smallest radiation burden should be used in children. Ultrasound to detect reflux meets several of these criteria. The development of echo enhancing agents has markedly improved reflux visualization by ultrasound. RESULTS: We discuss the clinical relevance of voiding urosonography. We reviewed the currently available literature and the results of our studies of this issue. We also describe our endeavors to avoid catheterization and detect vesicoureteral reflux based on various sonomorphological features, ie indirect voiding urosonography and ureteral jet Doppler waveform analysis, to avoid applying any substance into the bladder. CONCLUSIONS: Voiding urosonography is safe and reliable to detect vesicoureteral reflux. When indicated, considerably decreased radiation exposure can be achieved by voiding urosonography instead of established cystography methods. Indirect voiding urosonography and ureteral jet Doppler waveform analysis could be an alternative to invasive voiding cystography, at least in children older than 3 years.

Catheter-free methods for vesicoureteric reflux detection: our experience and a critical appraisal of existing data.

In recent years, the exact role of vesicoureteric reflux (VUR) in general has become controversial, though in some groups of children the knowledge of the existence or non-existence of VUR is still a very important issue. The number of techniques available for the assessment of VUR is increasing, and a new classification taking into account their real characteristics (direct/indirect, catheter-using/catheter-free, radiation-giving/radiation-free) has been proposed. The purpose of the following review is to evaluate the currently available evidence supporting the use of various catheter-free methods for VUR detection. We believe that as the clinical role of VUR has been questioned, it is even more important for the method of its detection to be user-friendly as regards catheterisation, radiation and availability. There is still no evidence supporting the assertion that any of the catheter-free methods of VUR detection might be the optimal one for any child. However, there are some groups of children who would benefit from using them. New studies using new, catheter-free methods of VUR detection or a combination of two or more of the methods described may prove useful in improving sensitivity and providing additional data on this important issue.

Sensitivity of ultrasonography in detecting renal parenchymal defects: 6 years' follow-up.

While (99m)Tc-dimercaptosuccinic acid (DMSA) scanning is still considered the most accurate method for the assessment of renal parenchymal defects (RPDs), our study 6 years previously suggested that ultrasonography (US) could be a safe and efficient substitute for this purpose, provided that it is reliably performed and that renal function parameters are followed. By comparison of the original and follow-up study data from 67 children, the accuracy of our recommendations was re-evaluated. US was performed and renal function parameters investigated and correlated to the DMSA scans from the original study. US identified all six patients with clinically significant RPD and 52/61 with clinically insignificant RPDs, seen on the DMSA scans. Twenty two out of 22 severe RPDs, 21/23 moderate RPDs and 20/40 mild RPDs seen on the DMSA scans were detected by US. In ten cases normal US findings from the original study were rendered abnormal, correlating well with the DMSA scans with respect to RPD localization and kidney size. These results further support our previous suggestion that US is a safe and harmless alternative to DMSA scanning in the detection and follow-up of RPDs. While it cannot be excluded that small RPDs missed on the initial US might 'develop' clinical significance in later life, children with normal findings on initial US should have another sonogram done, at the shortest a year later, together with an investigation of renal function parameters.

Publisher Correction: Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux.

Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations.

Effects of handgrip training and intermittent compression of upper arm veins on forearm vessels in patients with end-stage renal failure.

The purpose of our study was to assess the influence of handgrip training and intermittent compression of the upper arm veins on forearm arteries and veins. Eighteen chronic hemodialysis patients performed daily handgrip training for 8 weeks using a rubber ring, together with daily intermittent compression of the upper arm veins by elastic band. The forearm circumference, maximal handgrip strength, and arterial and vein parameters, including endothelium-dependent vasodilatation, were measured at the beginning, and after 4 and 8 weeks (using ultrasound scanning). The maximal handgrip strength and forearm circumference increased significantly. The radial artery diameters were significantly higher after 8 weeks of training (1.89 mm +/- 0.10 at the beginning, 1.95 +/- 0.10 mm after 8 weeks, P = 0.007), and endothelium-dependent vasodilatation was also found to be increased after 4 and 8 weeks of both activities. The venous parameters before tourniquet placement increased significantly after 8 weeks (2.40 +/- 0.16 mm at the beginning, 2.62 +/- 0.17 mm after 8 weeks, P = 0.014), and the venous parameters after tourniquet placement increased significantly after 4 and 8 weeks (3.36 +/- 0.17 mm at the beginning, 3.51 +/- 0.18 mm after 4 weeks, P = 0.009), 3.68 +/- 0.18 mm after 8 weeks, P < 0.001). The distensibility of veins was preserved. Our results showed that handgrip training and intermittent compression of the upper arm veins, performed daily, increase the diameter of forearm arteries and veins and improve endothelium-dependent vasodilatation.

Effect of intermittent compression of upper arm veins on forearm vessels in patients with end-stage renal disease.

Native arteriovenous fistula is the best vascular access for chronic hemodialysis. Primary and long-term success depends, in part, on the state of arteries and veins at the time of the operation. The aim of our study was to investigate the effects of intermittent compression of upper arm veins on forearm vessels in patients with terminal renal disease. The study group was composed of 16 chronic hemodialysis patients who performed daily intermittent compression of the upper arm without vascular access by elastic band (Eschmarch). Ten chronic hemodialysis patients were included in the control group, which performed no specific activity. Forearm measurements were obtained at the beginning of the study and 4 and 8 weeks later during the course of intermittent compression of the upper arm veins. The forearm circumference and maximal handgrip strength were measured. The artery measures, including endothelium-dependent vasodilatation and forearm vein variables, were obtained by ultrasonography measurements. The forearm circumference, maximal handgrip strength, and artery variables, including endothelium-dependent vasodilatation, remained unchanged. The basal venous diameters (2.29 +/- 0.19 mm at the beginning, 2.46 +/- 0.19 mm after 4 weeks, and 2.53 +/- 0.18 mm after 8 weeks) were significantly increased in the study group. The distensibility of veins was preserved in the study group. There were no significant changes in the control group. Our study demonstrated that daily intermittent compression of the upper arm veins increases the forearm vein diameter and preserves the distensibility of veins in patients with end-stage renal failure.

Long-term prospective evaluation of an inpatient voiding reeducation program for lower urinary tract conditions in children.

PURPOSE: Our aim was to evaluate the efficacy of our treatment program for children with lower urinary tract conditions, developed at the Department of Pediatric Nephrology of the University Children's Hospital in Ljubljana. METHODS: Sixty-four patients with lower urinary tract conditions were randomly allocated to two groups. Group A received treatment immediately, whereas patients of group B received no treatment for a period of 3 months-the amount of time it takes to complete our program. No child in group B experienced spontaneous regression of their symptoms in the 3-month delay period, while the patients of group A were already being treated and were achieving results. Thus, all the patients of group B then entered the program in exactly the same way as patients of group A. RESULTS: The final success rate in both groups did not differ significantly (p = 0.706-1.000) and ranged from 86.2 % for group A and 86.7 to 90 % for group B. Long-term follow-up showed statistically identical success rates (p = 1.000). CONCLUSION: This prospective controlled study with long-term follow-up (48 months) shows that our treatment program, applied as an inpatient voiding school program, is an effective method, with durable results.

Ureteric jet Doppler waveform: is it a reliable predictor of vesicoureteric reflux in children?

The purpose of our prospective study was to find out whether ureteric jet Doppler waveform (UJDW) could be a reliable predictor of vesicoureteral reflux (VUR) in children, compared with echo-enhanced voiding ultrasonography (VUS). Echo-enhanced VUS was performed in 75 children, 57 girls and 18 boys, aged 3 years to 12 years, following the accepted indications for this procedure. During the same procedure the measurement of UJDW was also performed and was considered to be successful (in 70 children) when at least ten UJDWs were recorded per ureteric unit. Depending on the shape of the UJDWs, the sequences were classified into three groups: monophasic, suggestive of VUR; complex, not suggestive of VUR; and mixed sequence, suggestive of VUR when a certain ratio between monophasic and complex UJDWs was achieved. When all three sequences were taken into account, the overall sensitivity and specificity of this method in detecting VUR were 88.5% and 82.3%, respectively. These values seem high enough for this method to be considered as a good alternative to invasive micturating cystographies in screening children for VUR.

Indirect voiding urosonography for detecting vesicoureteral reflux in children.

The purpose of our prospective study was to determine the value of indirect voiding urosonography without the use of contrast-media and without filling of the bladder through a catheter (IVUS) for detection of vesicoureteral reflux (VUR) in children, compared with echo-enhanced voiding urosonography (VUS). Among 57 children (45 girls and 12 boys, aged 2.7 to 12.0 years) admitted for echo-enhanced VUS either as part of routine evaluation after urinary tract infection (UTI) or follow-up of a previously detected VUR, IVUS was also successfully performed in 47 children. The results were considered positive when there was any increase in pelvis size and/or ureter lumen width during voiding. The overall sensitivity of IVUS in the detection of VUR was 49%, specificity 75%. The most accurate results were obtained with VUR grade III, where IVUS correctly detected 6 out of 7 cases, a sensitivity of 86%. The average increase of AP pelvis diameter during voiding was highly significant only in uretero-renal units with VUR grade III. Considering the obstacles in conducting the investigation and its relatively low overall sensitivity and specificity, it seems that IVUS is not sufficiently reliable to replace echo-enhanced VUS.

C1Q nephropathy in children.

C1q nephropathy (C1qNP) is a peculiar form of glomerulonephritis characterized by mesangial immunoglobulin and complement deposits, predominantly C1q, with no evidence of systemic lupus erythematosus. We describe the incidence, manifestation, histopathologic findings, follow-up, treatment and outcome of C1qNP. Twelve C1qNP patients were identified among 131 children who had undergone renal biopsy, accounting for a 9.16% incidence of C1qNP. Light microscopy examination showed focal segmental glomerulosclerosis (FSGS) with or without diffuse mesangial proliferation (n=6), minimal change disease (MCD) (n=4) or focal glomerulonephritis (n=2). C1q deposits were found in all, while electron microscopy revealed visible deposits in nine cases. Eight children presented with nephrotic syndrome, while one had nephrotic proteinuria and renal insufficiency that progressed to end-stage renal failure. The remaining three patients presented with nonnephrotic proteinuria associated with microhematuria, hypertension or renal insufficiency. Only one nephrotic syndrome patient responded excellently to corticosteroids, while four became corticosteroid dependent, and three were corticosteroid resistant, showing a very poor response to other immunosuppressive therapy as well. Patients with non-nephrotic proteinuria demonstrated fixed laboratory findings. Most C1qNP patients had FSGS or MCD, the majority of them presenting with corticosteroid-dependent or corticosteroid-resistant nephrotic syndrome. The latter showed a very poor response to any immunosuppressive therapy and high risk for progressive renal insufficiency.

Cyclic voiding urosonography in detecting vesicoureteral reflux in children.

Three methods are currently used to identify vesicoureteral reflux (VUR) in children, namely X-ray voiding cystourethrography (VCUG), radionuclide voiding cystography (RVC), and, recently, echo-enhanced voiding urosonography (VUS). It is known that the sensitivity of VCUG and RVC for detecting VUR can be improved by using cyclic procedures, such as repeated bladder filling and voiding. The purpose of our prospective study was to evaluate whether the cyclic procedure is superior to the conventional (one cycle only) procedure in VUS also. VUS was performed in 49 patients, aged 1.4-15.8 years (mean 4.1 years). After the first micturition, the catheter was left in place and the whole procedure was repeated under the same conditions. The results of the first and second cycles and the combined procedure were compared. In the initial cycle, 7 of 35 (20%) refluxing renal units that were detected in the second cycle and 4 of 26 (15%) children with at least unilateral VUR were missed. Cyclic VUS detected 25% more VURs than the conventional (one cycle only) VUS ( P=0.049) and revealed 50% more VUR III than the first cycle. Our results suggest that cyclic VUS is superior to conventional VUS.

Effect of local physical training on the forearm arteries and veins in patients with end-stage renal disease.

AIM: We investigate the effects of local training on the forearm vessels in patients with end-stage renal disease. METHODS: Fourteen hemodialysis patients were included. Handgrip training was performed for 8 weeks. The following parameters were measured at the beginning of the study and 4 and 8 weeks later: forearm circumference, maximal handgrip strength, and artery and vein parameters, including endothelium-dependent and endothelium-independent vasodilatation (using ultrasound and duplex Doppler scanning). RESULTS: The maximal handgrip strength increased significantly. The radial artery diameters were significantly higher after 8 weeks of training. The endothelium-dependent vasodilatation was found to be significantly increased after 4 and 8 weeks of training. The maximal vein diameters increased significantly with training, with preserved distensibility. CONCLUSIONS: The present study suggests that regular handgrip training increases the diameters of forearm vessels. It also improves endothelium-dependent vasodilatation. These changes point to the possible beneficial effects of daily handgrip training in chronic renal failure patients before arteriovenous fistula construction.

Erythrocyte deformability and microhematuria in children and adolescents.

The aim of this study was to investigate whether erythrocyte deformability is higher in otherwise healthy children and adolescents with asymptomatic isolated glomerular microhematuria and no clinical or laboratory signs indicating renal disorder. Erythrocyte deformability in 33 children and adolescents with unexplained asymptomatic isolated glomerular microhematuria (study group) was compared with erythrocyte deformability in 133 individuals without urinary tract disease and without microhematuria (control group), 26 patients with microhematuria and IgA nephropathy (IgA nephropathy group), and 31 children and adolescents with benign familial hematuria (benign familial hematuria group). The erythrocyte and buffer filtration time was measured, the erythrocyte-to-buffer filtration time ratio calculated, and, on the basis thereof, erythrocyte deformability was estimated as an inverse proportion of the erythrocyte-to-buffer filtration time ratio in all subjects. The erythrocyte-to-buffer filtration time ratio increased with age in all groups (P<0.001). In the study group, the mean erythrocyte-to-buffer filtration time ratio, corrected for age of subjects, was significantly lower than in the control (P=0.042), IgA nephropathy (P=0.004), and benign familial hematuria groups (P= 0.048). Erythrocytes with higher deformability probably pass more easily through the glomerular basement membrane that is assumed to be normal, in which case the mechanism of asymptomatic isolated glomerular microhematuria could be explained by higher erythrocyte deformability.

Sensitivity of ultrasonography in detecting renal parenchymal defects in children.

Renal parenchymal defects (RPD) -- scars, hypoplasia/dysplasia -- in children are a major risk factor for chronic renal failure. Most authors would agree that RPD should be detected and followed by a 99mTc-dimercaptosuccinic acid renal scan (DMSA), as ultrasonography (US) does not seem to be sensitive enough for this purpose. However, it might well be that DMSA is too sensitive and detects RPD that are too small to be clinically significant. The purpose of this study was to evaluate the sensitivity of US in identifying patients with clinically significant RPD and in detecting RPD of various grades as seen by DMSA. In 89 children with abnormal DMSA, a second DMSA, US, and other tests for evaluating renal function were performed at least 1 year after the first DMSA. The extent of RPD detected by DMSA and US was correlated with renal function parameters. In all 5 patients with diminished renal function, RPD were detected by both DMSA scan and US. In addition, US detected clinically insignificant RPD in 48 of 67 cases (71.6%). The present study has shown that, compared with DMSA, US is sensitive enough to detect clinically significant RPD in children. The substitution of DMSA with US would be beneficial, as this would eliminate radiation exposure, reduce costs, and increase availability.