Diversity of kidney care referral pathways in national child health systems of 48 European countries.

Background: Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. Methods: In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. Results: The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Conclusion: Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.

Clinical characteristics of Slovenian pediatric patients with autosomal recessive polycystic kidney disease.

AIMS: Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease. We reviewed the clinical characteristics, management, and outcomes in Slovenian pediatric patients with ARPKD. MATERIALS AND METHODS: All patients with ARPKD who were treated at the Pediatric Nephrology Department of the University Children's Hospital in Ljubljana between 1980 and 2020 were included in the study. The data were assessed retrospectively by reviewing the patients' medical records and analyzed using descriptive statistics. RESULTS: We included 13 patients, 6 boys and 7 girls. A prenatal diagnosis was established in 3 (23%) patients. In 4 (31%) patients, the diagnosis was confirmed within the first few days of life, while in 6 (46%) patients the disease manifested later during childhood. Four babies (31%) needed ventilatory support after birth. Arterial hypertension developed in all patients. Liver function was affected in 12 (92%) patients and was the predominant clinical concern in 2 of them. Two (15%) patients presented with end-stage renal disease (ESRD). Portal hypertension was found in 7 (54%) patients. Initial sonography revealed enlarged kidneys in 12 (92%) patients, hyperechoic kidneys or poor cortico-medullary differentiation in 10 (77%), and liver abnormalities in 5 (38%) patients. Unilateral nephrectomy was necessary before dialysis in 1 patient. Six (46%) patients started maintenance dialysis at an average age of 15.3 years. Kidney transplantation was performed in 2 (15%) and liver transplantation in 1 (8%) patient. Two (15%) patients died because of sepsis or respiratory failure. CONCLUSION: ARPKD is a progressive disease leading to ESRD and renal replacement treatment in almost half of our patients. Our data confirm the phenotypic variability of ARPKD in Slovenian patients.

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Clinical outcome is associated with the Urinary Tract Dilatation Classification System grade.

AIM: To assess the association between the Urinary Tract Dilatation (UTD) Antenatal (A) and Postnatal (P) Classification System grade and the outcome in term newborns. METHODS: This retrospective study enrolled 166 term newborns (71% boys, 206 ureterorenal units) evaluated for unilateral or bilateral UTD in the Neonatology Department of Ljubljana University Medical Center from 2012 to 2018. Data on family history, sex, gestational age, birth weight, head circumference, Apgar score, possible oligohydramnios, indication for and age at first postnatal ultrasound, time of follow-up, and clinical outcome were collected. Radiology records were reviewed to grade UTD according to the Multidisciplinary Consensus on the Classification of Prenatal and Postnatal UTD. RESULTS: The majority of ureterorenal units with UTD A 2-3 had UTD P 2 or 3. Spontaneous resolution, specific uropathy, the need for surgery, and the risk of urinary tract infection were all significantly associated with the UTD P grade. No patient experienced renal dysfunction at the end of follow-up (12-48 months, median 24 months), and therefore this parameter was not associated with the UTD P grade. CONCLUSIONS: The UTD grade was associated with the probability of spontaneous resolution, time to its occurrence, specific uropathies urinary tract infection, and risk for surgery. However, no association with renal dysfunction was established.

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

BACKGROUND: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. METHODS: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. RESULTS: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. CONCLUSIONS: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy.

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

Does the duration of ambulatory blood pressure measurement matter in diagnosing arterial hypertension in children?

OBJECTIVES: The aim of our study was to establish if 48-hour ambulatory blood pressure monitoring (ABPM) is more reliable than 24-hour monitoring in order to reduce the impact of external factors on blood pressure (BP) in children. METHODS: Two hundred fifteen children with indications for ABPM underwent 48-hour ABPM. In the first part of the study, the values of systolic BP (SBP), diastolic BP (DBP) and heart rate between the first 24 hours and the total 48 hours were compared. In the second part, the same parameters between the first and second 24 hours were compared. In the third part, we determined whether the differences in measurements between the first and second 24 hours had clinical significance and meant a change of diagnosis. RESULTS: The results of the first part of the study showed no statistically significant differences. In the second part, the average values of SBP and DBP were statistically significantly higher during the first 24 hours as compared with the second 24 hours. In the second 24 hours, more children had normal BP (NBP) and a smaller number of them had high NBP or arterial hypertension (AH) compared with the first 24 hours, suggesting that this has clinical significance. CONCLUSIONS: Within certain limits, the results of our study suggest that 48-hour ABPM is more reliable than 24-hour ABPM, where especially the second 24 hours are a period of measurement that should be taken into consideration for this purpose. These results could impact the diagnostics of AH in children.

Severe active C3 glomerulonephritis triggered by immune complexes and inactivated after eculizumab therapy.

BACKGROUND: Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a dramatic shift in its classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN, consisting of dense deposit disease and C3 glomerulonephritis (C3GN). A limited number of C3GN cases have been published to date with not yet conclusive results since the novel therapeutic approach with eculizumab was introduced. CASE PRESENTATION: We report the clinical follow-up of a 16-year-old patient in whom a diagnosis of C3GN was confirmed by immunofluorescence and electron microscopy in second and third kidney biopsies, while the first biopsy revealed idiopathic immune complex-mediated MPGN type III, Anders and Strife variant, which failed to improve after several attempts at conventional immunosuppression therapy. Although applied late in an already fairly advanced stage of the severe active form of MPGN, the efficacy of eculizumab on C3GN was evidenced clinically and pathohistologically. Its beneficial influence on pathomorphogenesis was demonstrated by a unique follow-up in the last three biopsies, despite the recent observation, confirmed in this study, of eculizumab binding within the kidney tissue. CONCLUSIONS: Clinicians and pathologists should be aware that, in some patients, an underlying genetic or acquired complement alternative pathway abnormality can be masked by an initial immune complex-mediated mechanism, which subsequently triggers an unbalanced excessive continual driving of complement terminal pathway activation and the development of C3GN. In such a patient, supplementary steroids in addition to eculizumab appear necessary to achieve an adequate response.

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.

Post-vaccine glomerulonephritis in an infant with hereditary C2 complement deficiency: case study.

We describe a case of a post vaccine immune complex-mediated glomerulonephritis in an infant with compound heterozygous mutations of C2 complement component gene, which is the first such case in the literature. The three and a half months old boy presented with clinical and laboratory signs of nephritic syndrome and was successfully treated with methylprednisolone. An explanation of such a clinical picture may lie in the interaction between C2 deficiency and vaccination.

Double venous drainage through the superior vena cava in minimally invasive aortic valve replacement: a retrospective study.

AIM: To compare the outcomes of patients who underwent upper mini-sternotomy or right mini-thoracotomy and those who underwent full sternotomy and to report a technical improvement in venous drainage by means of double venous cannulation of the superior vena cava (SVC) in mini surgical procedures. METHODS: We retrospectively analyzed the outcome of 217 patients who underwent aortic valve replacement through upper mini-sternotomy or right mini-thoracotomy at the Department of Cardiovascular Surgery, University Medical Centre Ljubljana, Slovenia from 1996 till 2010. Cannulation of SVC and right atrial appendage was performed in 142/217 (65%) patients, while in the remaining 75 (35%) patients, double cannulation of SVC was used for venous drainage. The results of patients who underwent mini approaches were compared to 236 patients who underwent full sternotomy for the same purpose from 2009 to 2010 at the same center. RESULTS: We found a shorter mean length of intensive care unit stay, less volume chest-tube drainage, shorter crossclamp and cardio pulmonary bypass times, and less postoperative permanent pacemaker implantations in the minimally invasive group patients than in full sternotomy group patients. Using double cannulation of the SVC for venous drainage made venous cannulation in mini approaches easier and eliminated the need for obtaining femoral venous access. CONCLUSION: Our study confirmed that even though technically challenging, upper mini-sternotomy and right mini-thoracotomy approaches for aortic valve replacement have potential advantages over conventional median sternotomy. They were proved to be safe, efficacious, and can significantly reduce surgical trauma and are therefore particularly valuable in some higher risk, obese, diabetic and elderly patients. Using double cannulation of SVC for venous drainage made venous cannulation easier and eliminated the need for obtaining femoral venous access.

A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life.

BACKGROUND: Second-generation echo-enhanced voiding urosonography (VUS) with improved contrast-specific ultrasound (US) techniques is increasingly being used for vesicoureteric reflux (VUR) detection. AIM: To compare VUS with X-ray voiding cystourethrography (VCUG) and to evaluate the predictive value of pelvicalyceal dilatation for detecting VUR in the first year of life. MATERIALS AND METHODS: Sixty-six children younger than one were investigated by US, VUS and VCUG. VCUG represented the reference method for VUR detection. RESULTS: According to VCUG, VUR was present in 16/132 (12%) renal units. VUS confirmed all these and additionally revealed VUR in 26 renal units (all together 42/132 (32%) renal units with VUR). It should be noted that all VUR detected only with VUS and missed by VCUG were of grades II and III. In 27/92 (29%) US normal and in 15/40 (37%) renal units with pelvicalyceal dilatation, VUR was detected by VUS. CONCLUSION: We believe that VUS could safely replace VCUG in VUR detection in infants, with no regard to the degree of abnormality of the upper urinary tract seen on US. VCUG should be limited only to cases where bladder and/or urethra pathology are suspected.

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.

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.

Rare variant of Lesch-Nyhan syndrome without self-mutilation or nephrolithiasis.

Lesch-Nyhan syndrome is a very rare X-linked recessive disorder characterized by mental retardation, spasticity resembling cerebral palsy, choreo-athetosis, self-mutilation and hyperuricemia. Self-mutilative behavior is a hallmark of the disease. Hyperuricemia leads to hyperuricuria and uric acid nephrolithiasis. The underlying defect is a deficiency of hypoxanthine-guanine-phosphoribosyl transferase. We report on a 7-year-old boy with Lesch-Nyhan syndrome, lacking self-mutilative behavior, who was erroneously diagnosed as having athetotic cerebral palsy. He also had no renal stones; hyperechoic renal medullary pyramids were the only renal abnormality detected and were sonographically indistinguishable from medullary nephrocalcinosis.

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.