Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.

Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.

Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.

Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.

C3 glomerulopathy in children: Is there still a place for anti-cellular immunosuppression?

AIM: To contribute additional clinical experience to the paucity of reports on C3 glomerulopathy (C3GP) in children, we are reporting our cohort of 11 children with C3GP, emphasizing the therapeutic options in this peculiar entity. METHODS: We describe the incidence, manifestation, histopathology findings, follow-up, treatment and outcome of C3GP in 11 children with C3GP by retrospectively analyzing their clinical charts and renal biopsy reports. RESULTS: Eleven C3GP patients were identified among 240 children who had undergone renal biopsy, accounting for a 4.6% incidence of C3GP. A light microscopy examination showed a membranoproliferative pattern (n = 8), mesangial proliferation (n = 1), a mesangial/membranoproliferative pattern (n = 1) and endocapillary proliferation (n = 1). All children presented with proteinuria of varying degrees, the majority of them with additional hematuria, three with full-blown nephrotic-nephritic syndrome, and two with renal insufficiency at presentation. Very diverse treatments were applied in our cohort of patients, from no specific treatment to different mono or combined anti-cellular immunosuppression treatments, as well as a trial of plasma therapy or eculizumab. Our results are in to some extend in concordance with other studies revealing that an optimal therapy for C3GP is still unknown, but we believe that a trial of classical immunosuppression before eculizumab is still worth trying, while eculizumab can have a beneficial effect, but not in all patients. CONCLUSION: A diverse histological pattern and clinical picture and no known optimal therapy are a hallmark of C3GP.

Vesicoureteral refux detection in children: a comparison of the midline-to-orifice distance measurement by ultrasound and voiding urosonography.

BACKGROUND: Due to the questionable clinical role of vesicoureteral reflux (VUR) and the search for noninvasive, radiation-free procedures sufficiently reliable to detect VUR, we compared the correlation between the midline-to-orifice distance (MOD) measured by ultrasonography (US) and echo-enhanced voiding urosonography (VUS) for detecting VUR in children. The aim of the study was to determine whether measuring MOD by US could be a reliable predictor of VUR in children. METHODS: A total of 116 children, aged 0.25-84 months, with 232 potentially refluxing units were investigated simultaneously by measuring the MOD and performing VUS. Indications for cystography were urinary tract infection and follow-up of a previously detected VUR. VUS was performed after the MOD measurement. The results were analyzed with VUS as the reference method. RESULTS: The MOD was significantly larger in VUR grade III (10.7 mm; p = 0.003) and VUR grade II (9.9 mm; p = 0.001) refluxing units than in non-refluxing units (7.8 mm), even when controlling for the estimated volume/expected maximal capacity (Vest/Vmax) ratio. A MOD cutoff value of 7.4 mm was chosen as a predictor of either the presence or absence of VUR; the sensitivity and specificity of this cutoff measurement for VUR detection were found to be 89 and 24%, respectively. CONCLUSIONS: Despite the statistically significant difference between the MOD of refluxing versus non-refluxing units identified in our study, the MOD measurement needs further evaluation to determine its potential value as a diagnostic tool for the detection of VUR.

Long-term outcome after combined or sequential liver and kidney transplantation in children with infantile and juvenile primary hyperoxaluria type 1.

Introduction: Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare. Methods: All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively. Results: Eighteen patients (infantile PH1 n = 10, juvenile PH1 n = 8) underwent transplantation (CLKT n = 17, SLKT n = 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1), P = 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 (P = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, P = 0.59). Discussion: In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.

The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results.

BACKGROUND: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically. RESULTS: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases. CONCLUSIONS: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

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.

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.

Pathology, clinical presentations, and outcomes of C1q nephropathy.

C1q nephropathy is an uncommon glomerular disease with characteristic features on immunofluorescence microscopy. In this report, clinicopathologic correlations and outcomes are presented for 72 patients with C1q nephropathy. The study comprised 82 kidney biopsies from 28 children and 54 adults with male preponderance (68%). Immunofluorescence microscopy showed dominant or co-dominant staining for C1q in the mesangium and occasional glomerular capillary walls. Electron-dense deposits were observed in 48 of 53 cases. Light microscopy revealed no lesions (n = 27), focal segmental glomerulosclerosis (FSGS; n = 11), proliferative glomerulonephritis (n = 20), or various other lesions (n = 14). Clinical presentations in the patients who had no lesions histology were normal urine examination (7%), asymptomatic hematuria and/or proteinuria (22%), and nephrotic syndrome (minimal change-like lesion; 63%), which frequently relapsed. All patients with FSGS presented with nephrotic syndrome. Those with proliferative glomerulonephritis usually presented with chronic kidney disease (75%) or asymptomatic urine abnormalities (20%). Of the patients with sufficient follow-up data, complete remission of the nephrotic syndrome occurred in 77% of those with a minimal change-like lesion, progression to end-stage renal disease occurred in 33% of those with FSGS, and renal disease remained stable in 57% of those with proliferative glomerulonephritis. In conclusion, this study identified two predominant clinicopathologic subsets of C1q nephropathy: (1) Podocytopathy with a minimal change-like lesion or FSGS, which typically presents with nephrotic syndrome, and (2) a typical immune complex-mediated glomerular disease that varies from no glomerular lesions to diverse forms of glomerular proliferation, which typically presents as chronic kidney disease. Clinical presentation, histology, outcomes, and presumably pathogenesis of C1q nephropathy are heterogeneous.

Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients.

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation, characterized by hemolytic anemia, thrombocytopenia and acute renal failure. Mutations in complement inhibitors are major risk factors for development of aHUS. The three aHUS patients reported in this study had several previously identified alterations in complement inhibitors; e.g. risk haplotypes in CD46 and factor H but we also identified two novel heterozygous non-synonymous CD46 alterations (p.E142Q and p.G259V). Presence of G259V caused decreased expression of the recombinant mutant CD46 compared to wild type (WT). Western blot analysis showed that the majority of the expressed G259V protein was in the precursor form, suggesting that it is processed less efficiently than WT. Low CD46 expression on the surface of the patient's neutrophils confirmed the in vitro results. Further, G259V had a substantially impaired ability to act as a cofactor to factor I, in the degradation of both C3b and C4b. The E142Q mutant showed neither decreased expression nor impaired function. Two of the patients also had a heterozygous non-synonymous alteration in factor H (p.Q950H), reported previously in aHUS but not functionally tested. This variant showed moderately impaired function in hemolytic assays, both using patient sera and recombinant proteins. The recombinant Q950H also showed a somewhat decreased expression compared to WT but the complement inhibitory function in fluid phase was normal. Taken together, we report a novel CD46 alteration showing both a decreased protein expression and substantially impaired cofactor function (G259V) and another without an effect on expression or cofactor function (E142Q). Moreover, mild consequences of a previously reported aHUS associated rare variant in factor H (Q950H) was also revealed, underlining the clear need for functional characterization of each new aHUS associated mutation.

Mid-aortic syndrome in a 3-year-old girl successfully treated by aorto-aortic grafting and renal artery implantation into the graft.

Mid-aortic syndrome, an uncommon acquired or congenital condition characterized by segmental narrowing of the abdominal or distal descending thoracic aorta, is frequently accompanied by ostial stenosis of the aorta's branches. If left untreated, it can result in life-threatening complications secondary to severe hypertension.We report the case of a 3-year-old girl with congenital mid-aortic syndrome, who was diagnosed by chance in the course of a viral illness, and whose high blood pressure values were first dismissed as inaccurate. Attempts to achieve medical or endovascular control of her hypertension were unsuccessful. She was thereafter successfully treated by aorto-aortic bypass grafting, resection of the stenotic segments of both renal arteries, and implantation of the patent arterial segments into the graft.

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.