Early diagnosis of solitary functioning kidney: comparing the prognosis of kidney agenesis and multicystic dysplastic kidney.

BACKGROUND: Individuals with congenital solitary functioning kidney (SFK) are at an increased risk of kidney damage. According to some studies, the risk is higher in unilateral kidney agenesis (UKA) than in unilateral multicystic dysplastic kidney (UMCDK). We hypothesized that with early detection of children with UKA and UMCDK, there would be no difference in the presence of hypertension, proteinuria, and reduced glomerular filtration rate (GFR) between UKA and UMCDK. METHODS: Based on a long-term follow-up protocol, we evaluated a cohort of 160 children followed from birth for SFK (84 with UKA and 76 with UMCDK) detected by prenatal or routine neonatal ultrasound screening. Hypertension, proteinuria, and reduced GFR were monitored as markers of kidney damage. We compared the characteristics and outcomes of the subgroups of children with UKA and UMCDK. RESULTS: GFR was reduced in 42 (26.2%) children, of whom 41 showed only mild reduction. Hypertension and proteinuria were found in 22 (13.8%) and 14 (8.8%) children, respectively. Combined kidney damage was present in 57 (35.6%) children. The UMCDK and UKA subgroups differed in GFR at final examination, with UMCDK patients being significantly more likely to have normal GFR compared to UKA patients (82% vs. 67%; p = 0.039). CONCLUSIONS: One third of the children showed signs of SFK damage, albeit mild. Patients with UKA had reduced GFR significantly more often than those with UMCDK, but did not differ in the rates of hyperfiltration injury or congenital anomalies of the kidneys and urinary tract (CAKUT) in SFK.

Juvenile Primary Sjögren Syndrome in a 15-Year-Old Boy with Renal Involvement: A Case Report and Review of the Literature.

Juvenile primary Sjögren syndrome (pSS) with renal involvement is extremely rare, reported approximately in 50 children, predominantly girls. Here, we present the first reported case of a male child with juvenile pSS with ocular surface disease (previously keratoconjunctivitis sicca), submandibular salivary gland involvement, and tubulointerstitial nephritis. First, two symptoms were clinically apparent at presentation. We illustrate here that kidney involvement in pSS should be actively looked for, as juvenile pSS may be associated with asymptomatic renal involvement. Immunophenotyping of peripheral blood cells using multicolor flow cytometry revealed at the time of diagnosis changes in both adaptive (T memory cells and B memory cells), and innate immunity (an increased activation of natural killer cells, as well as monocytes and neutrophils, and an increased representation of intermediate monocytes). Our case report points to the importance of kidney examination, early diagnosis and therapy in juvenile pSS, as well as highlights international collaboration to obtain more data for this rare disease.

Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis as a Complication of Home Parenteral Nutrition.

Patients on long-term home parenteral nutrition (HPN) occasionally develop glomerulonephritis due to chronic central venous catheter (CVC)-related infection. Most previously reported cases were membranoproliferative glomerulonephritis (MPGN). This is a case report of a 16-year-old girl receiving HPN for short bowel syndrome. After 11 years on HPN, she developed acute kidney injury with macroscopic hematuria, nephrotic-range proteinuria, and a reduced glomerular filtration rate (GFR). Initially, MPGN associated with chronic bacteremia was suspected with the assumption that the condition would be treated with antibiotics and CVC replacement. However, her kidney biopsy revealed antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAG). This was consistent with the fact that the patient tested positive for proteinase 3-ANCA. Immunosuppressive therapy with methylprednisolone pulses (followed by oral prednisone) and rituximab led to remission. Her GFR and protein excretion returned to normal. Chronic bacteremia as a complication of long-term HPN may cause various types of glomerulonephritis including, rarely, AAG requiring immunosuppressive therapy.

The use of biomarkers in the diagnosis and treatment of obstruction of the upper urinary tract in children.

Antenatal hydronephrosis, dilatation of the upper urinary tract (UUTD), is a common finding on prenatal ultrasound. One of the most common causes is ureteropelvic junction (UPJ) obstruction. Although such prenatally diagnosed UUTD resolves spontaneously in most newborns, further examination of these children is advocated to prevent possible irreversible kidney damage, and ultrasound is mainly used for this. If the dilatation persists or becomes symptomatic, it is necessary to proceed to other relatively demanding and invasive diagnostic examinations for these small patients, where the question of the right timing of indications for possible surgical solutions is still unclear. For this reason, various biomarkers have been investigated in a number of clinical trials as potential mini-invasive diagnostic tools for determining when upper urinary tract dilatation in such children poses a threat to the developing kidneys and they should be operated on, and vice versa, when to proceed conservatively. The aim of this article is to review the findings on and current issues with the use of biomarkers in the diagnosis and treatment of UPJ obstruction in children.

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.

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.

Isolated low initial differential renal function in patients with primary non-refluxing megaureter should not be considered an indication for early surgery: A multicentric study.

INTRODUCTION: Low initial differential renal function (DRF) in patients with primary non-refluxing megaureter (PNRM) is considered an indication for surgery as are an increase of dilatation and symptoms. OBJECTIVE: We hypothesized that low DRF is not necessarily a result of obstruction, but may be due to impaired development of the upper urinary tract. Thus, in the absence of symptoms, there is a low risk for further loss of renal function. This study aimed to assess whether initially low DRF is a reliable indicator of obstruction. STUDY DESIGN: We reviewed data from four university centers between 1995 and 2010. Patients under 12 months of age with unilateral primary non-refluxing megaureter (PNMR) and a DRF between 10% and 40%, and followed minimally 24 months, were included. Patients were placed in two groups based on management: group A, surgical; group B, conservative. The dynamics of DRF in relation to age and type of treatment was studied. In each patient we recorded the earliest (initial) DRF, the last known (final) DRF, the age when MAG-3 scans were performed and the type of treatment. RESULTS: From 25 patients, 16 were treated surgically (group A) and 9 followed conservatively (group B). The initial mean DRF in group A was 33.1% and in group B 34.5%, at a mean age 3.0 and 3.6 months, respectively. The final mean DRF in group A was 40.1% and in group B 43%, at a mean age 59.9 and 46.3 months, respectively. Using two-way repeated ANOVA (age [initial DRF, final DRF] vs. group [group A, group B]), we found non-significant difference between the groups in the DRF, F (1, 21) = 0.96, p = 0.338, while we observed statistically significant and similar increase from the initial to final DRF in both groups, F (1, 21) = 16.66, p = 0.001 (Figure). DISCUSSION: This is the first study focusing on the evolution of renal function in patients with PNRM and low initial DRF. Results suggest that the diagnosis of obstruction is inaccurate in most infants with unilateral PNRM if it is based on low initial DRF only. Renal deterioration rarely occurs in asymptomatic patients, and even profoundly impaired kidneys have potential for improvement. Limitations of our study include retrospective design and lack of standardization of treatment among the four centers. CONCLUSION: Low DRF in asymptomatic and anatomically stable patients with PNMR should not be considered an indication for early surgery. These findings challenge current practice and should be confirmed by a prospective study.

Can renal ultrasonography and DMSA scintigraphy be used for the prediction of irreversible histological lesions of the upper pole in duplex system with ureteroceles or ectopic ureters?

AIM: To assess of the role of renal ultrasonography (US) and DMSA renal scintigraphy in the prediction of irreversible histological lesions of the upper pole in duplex system. METHODS: A prospective cohort study based on data collected between 2005 and 2012 at our institution. The cohort consisted of 23 patients with ureteroceles and 28 patients with ectopic ureters who underwent upper pole nephrectomy. Preoperative recordings from ultrasound and nuclear renal scans were compared with the histological findings. Histological irreversible lesions were defined as the presence of dysplasia and/or severe chronic interstitial nephritis (CIN) in ≥ 90% of the specimen. ROC (Receiver Operating Characteristic) curves were used to investigate thresholds in order to identify irreversible lesions using various differential functions. The histology was correlated with the results of imaging. RESULTS: Pathological findings were found in all histological samples. Histological lesions were irreversible in 20/23 patients (87.0%) with ureteroceles and in 14/28 patients (50.0%) with ectopic ureters. The model is able to predict irreversible lesions if an upper pole differential function is ≤ 3% in patients with ureteroceles, and ≤ 2% in the presence of ectopic ureters. Weak association between parenchymal thinning on ultrasonography and irreversible lesions was found in patients with ectopic ureters. CONCLUSION: DMSA renal scintigraphy provides a useful tool for the prediction of irreversible lesions in the upper pole. Low differential function (≤ 3% and ≤ 2%, respectively) indicates irreversible lesions, favoring heminephrectomy. Higher differential function indicates greater remaining biological potential of the parenchyma, favoring reconstruction of the upper pole.

Renal parenchymal thickness in children with solitary functioning kidney.

BACKGROUND: Reduced renal parenchymal thickness (PT) is a parameter used by clinicians to assess the degree of hydronephrosis. In patients with a congenital hydronephrotic solitary functioning kidney (SFK), PT is difficult to determine as there is no comparison with the contralateral kidney. The aim of this study was to obtain ultrasound measurements of PT in children with normal SFK and to compare these data with PT measurements in children with two functioning kidneys. METHODS: This was a prospective multicenter study carried out between 2006 and 2011 in which 236 children aged 11 days to 18.96 years with healthy SFK were examined. The SFK etiologies were unilateral renal agenesis or a nonfunctioning contralateral kidney, mostly due to multicystic dysplasia. In addition to determining other parameters, we measured PT in the middle third of the kidney by ultrasound. Correlations between PT and age, height and weight were assessed. RESULTS: Correlation analysis showed a positive correlation with renal PT for all parameters. The correlation coefficients for age, height and weight were 0.863, 0.873 and 0.874, respectively. In most age categories, the renal parenchyma was significantly thicker in the SFK than in two functioning kidneys. CONCLUSIONS: Based on our results, we suggest that PT in the SFK is correlated with height, weight and age of the patient. Consequently, measurements of PT may be used for monitoring the development of the healthy SFK and may contribute to a more accurate assessment of the severity of SFK anomalies.

Copy-number disorders are a common cause of congenital kidney malformations.

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Diagnostic accuracy of postnatal ultrasound screening for urinary tract abnormalities.

The study was aimed at (1) the determination of the incidence of abnormalities of the urinary tract in newborn infants detected by postnatal ultrasound screening, and (2) the evaluation of the diagnostic accuracy of postnatal ultrasound screening for detecting surgical urinary tract abnormalities. The prospective study was of full-term neonates born in the University Hospital of Olomouc in 2005-2008 who underwent renal ultrasound screening after 72 h of life. Significant findings were recorded. Subsequent diagnostic and therapeutic procedures were recorded and evaluated in a group of children with detected renal pelvic dilatation (RPD). (1) A total of 6,088 newborn infants was examined. The absolute and relative RPD incidence rates (anteroposterior diameter, APD) were as follows: 5-7 mm, 146 (2.4%); 7-10 mm, 70 (1.15%); 10-15 mm, 13 (0.21%), and 15 mm or more, 5 (0.08%). Of those, 16 children were operated on for abnormalities of the urinary tract, of which nine (56%) had been detected by prenatal screening. Other findings: six cases of unilateral renal agenesis, four cases of multicystic renal dysplasia, four of renal dystopia, one of polycystic kidney disease and one of renal hypoplasia. (2) A group of 224 children with postnatally detected RPD was examined, of whom 40 (17.9%) underwent voiding cystourethrography and/or scintigraphy and 16 (7.1%) were treated surgically. The receiver operating characteristic curves were analyzed, and the areas under the curves were calculated. Postnatal renal ultrasound screening is probably a suitable test for detecting significant urinary tract abnormalities.

Regression of left-ventricular hypertrophy in children and adolescents with hypertension during ramipril monotherapy.

BACKGROUND: Left-ventricular hypertrophy (LVH) is a risk factor for cardiovascular morbidity. Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) is able to induce the regression of LVH in adults. However, there has been no study of the ability of ACEI to induce the regression of LVH in children. Our aim was to investigate the effect of ramipril on left-ventricular mass and blood pressure (BP) in hypertensive children. METHODS: Twenty-one children (median age, 15 years) with renal (76%) or primary (24%) hypertension were prospectively treated with ramipril monotherapy for 6 months. Blood pressure was evaluated using ambulatory BP monitoring, with hypertension defined as mean BP >or=95th percentile. Left-ventricular hypertrophy was defined either as left-ventricular mass index (LVMI) >38.6 g/m(2.7) (pediatric definition) or as LVMI >51.0 g/m(2.7) (adult definition). RESULTS: Nineteen children completed the study. The median LVMI decreased from 36.8 g/m(2.7) (range, 18.9 to 55.8 g/m(2.7)) to 32.6 g/m(2.7) (range, 19.0 to 52.1 g/m(2.7); P < .05) after 6 months. The prevalence of LVH decreased from 42% to 11% using the pediatric definition (P < .05) and did not change using the adult definition (ie, it remained at 5%). The median ambulatory BP decreased by 11, 7, 8, and 7 mm Hg for daytime systolic, daytime diastolic, nighttime systolic, and nighttime diastolic BP (P < .05), respectively. A positive correlation was found between LVMI and nighttime systolic BP at the start of the study (r = 0.46, P < .05). CONCLUSIONS: Ramipril is an effective drug in children with hypertension, for its ability to reduce not only BP but also left-ventricular mass and induce regression of LVH.

Ramipril in the treatment of hypertension and proteinuria in children with chronic kidney diseases.

BACKGROUND: Angiotensin-converting enzyme inhibitors are the drugs of choice in renal hypertension. The efficacy and safety of ramipril in adults has been proved; however, data on effectiveness of ramipril in children are few. The aim of the present study was to investigate the effect of ramipril on blood pressure (BP) and proteinuria in children with chronic kidney diseases. METHODS: A total of 31 children (median age 11.3 years, range 1.9-19.8 years) with various chronic nephropathies and hypertension or proteinuria were prospectively treated with ramipril for 6 months. Blood pressure was evaluated using ambulatory BP monitoring and hypertension was defined as mean BP equal to or greater than the 95th percentile for healthy children. Proteinuria was defined as protein excretion > or =100 mg/m(2)/24 h. The starting dose of ramipril was 1.5 mg/m(2)/24 h once daily. In 27 children it was given as monotherapy. RESULTS: The median decrease in ambulatory BP was 11 mm Hg for daytime systolic, 10 mm Hg for daytime and nighttime diastolic, and 8 mm Hg for nighttime systolic BP. Hypertension normalized in 55% of the children. Proteinuria decreased in 84% of the children with pathologic proteinuria; the median decrease was 51%. A positive correlation was found between initial proteinuria and change of proteinuria (r = 0.95, P <.001). Glomerular filtration rate and serum potassium level did not change significantly. One child developed a cough that was believed to be related to ramipril. CONCLUSIONS: Ramipril is an effective and safe drug in children with chronic kidney diseases associated with hypertension, proteinuria, or both.