Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D ...catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.
Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches ...adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype–phenotype correlations propose that the location and character of the individual's ...variant correlate with the renal outcome and any extra renal manifestations. In‐depth clinical and genetic data of 60/62 children who participated in the EARLY PRO‐TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X‐linked inheritance were then classified according to the severity of their COL4A5 variant into less‐severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less‐severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less‐severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable ...and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.
Congenital anomalies of the kidneys and urinary tract (CAKUTs) are one of the most prevalent primary causes of end-stage renal disease (ESRD) in young children, and approximately one-third of these ...children present with lower urinary tract dysfunction (LUTD). Many children with LUTD require therapy with clean intermittent catheterization (CIC). CIC commonly leads to bacteriuria, and considerations have arisen regarding whether CIC in immunosuppressed children is safe or whether repeated febrile urinary tract infections (UTIs) may lead to the deterioration of kidney graft function.
We retrospectively reviewed all cases of primary kidney transplantation performed in our center between 2001 and 2020 in recipients aged less than twelve years. The number of episodes of febrile UTIs as well as the long-term kidney graft survival of children undergoing CIC were compared to those of children with urological causes of ESRD not undergoing CIC, as well as to those of children with nonurological causes of ESRD.
Following successful kidney transplantation in 41 children, CIC was needed in 8 of these patients. These 8 children undergoing CIC had significantly more episodes of febrile UTIs than did the 18 children with a nonurological cause of ESRD (
= 0.04) but not the 15 children with a urological cause of ESRD who did not need to undergo CIC (
= 0.19). Despite being associated with a higher rate of febrile UTIs, CIC was not identified as a risk factor for long-term kidney graft survival, and long-term graft survival did not significantly differ between the three groups at a median follow-up of 124 months.
Our study demonstrates that, under regular medical care, CIC following pediatric transplantation is safe and is not associated with a higher rate of long-term graft loss.
Recognizing risk factors that may negatively affect long-term graft survival following pediatric kidney transplantation is a key element in the decision-making process during organ allocation. We ...retrospectively reassessed all cases of pediatric kidney transplantation performed in our center in the last 20 years with the aim of determining baseline characteristics that could be identified as prognostic risk factors for long-term graft survival. Between 2001 and 2020, a total of 91 kidney transplantations in children under the age of 18 years were undertaken in our center. Early graft failure was observed in six of the 91 patients (7%). The median follow-up of the remaining 85 children was 100 months, and the overall kidney graft survival rates at 5, 10, 15 and 20 years were 85.2%, 71.4%, 46.0% and 30.6%, respectively. Small children with a body surface area of <1 m2 were significantly associated with better long-term graft survival outcomes, while adolescents aged more than twelve years showed poorer graft survival rates than younger children. Body surface area of the recipient of ≥1 m2, pretransplantation duration of the recipient on dialysis ≥18 months, hemodialysis prior to transplantation and donor/recipient age difference of ≥25 years were significantly associated with poorer long-term graft survival.
Nerve injury triggers numerous changes in the injured neurons and surrounding nonneuronal cells that ultimately result in successful target reinnervation or cell death. c-Jun is a component of the ...heterodimeric AP-1 transcription factor, and c-Jun is highly expressed in response to neuronal trauma. Here we have investigated the role of
c-jun during axonal regeneration using mice lacking
c-jun in the central nervous system. After transection of the facial nerve, the absence of c-Jun caused severe defects in several aspects of the axonal response, including perineuronal sprouting, lymphocyte recruitment, and microglial activation. c-Jun-deficient motorneurons were atrophic, resistant to axotomy-induced cell death, and showed reduced target muscle reinnervation. Expression of CD44, galanin, and α7β1 integrin, molecules known to be involved in regeneration, was greatly impaired, suggesting a mechanism for c-Jun-mediated axonal growth. Taken together, our results identify c-Jun as an important regulator of axonal regeneration in the injured central nervous system.
Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the ...pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases.
We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters.
The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.
J. Neurochem. (2012) 121, 607–618.
Although neural c‐Jun is essential for successful peripheral nerve regeneration, the cellular basis of this effect and the impact of c‐Jun activation are ...incompletely understood. In the current study, we explored the effects of neuron‐selective c‐Jun deletion, substitution of serine 63 and 73 phosphoacceptor sites with non‐phosphorylatable alanine, and deletion of Jun N‐terminal kinases 1, 2 and 3 in mouse facial nerve regeneration. Removal of the floxed c‐jun gene in facial motoneurons using cre recombinase under control of a neuron‐specific synapsin promoter (junΔS) abolished basal and injury‐induced neuronal c‐Jun immunoreactivity, as well as most of the molecular responses following facial axotomy. Absence of neuronal Jun reduced the speed of axonal regeneration following crush, and prevented most cut axons from reconnecting to their target, significantly reducing functional recovery. Despite blocking cell death, this was associated with a large number of shrunken neurons. Finally, junΔS mutants also had diminished astrocyte and microglial activation and T‐cell influx, suggesting that these non‐neuronal responses depend on the release of Jun‐dependent signals from neighboring injured motoneurons. The effects of substituting serine 63 and 73 phosphoacceptor sites (junAA), or of global deletion of individual kinases responsible for N‐terminal c‐Jun phosphorylation were mild. junAA mutants showed decrease in neuronal cell size, a moderate reduction in post‐axotomy CD44 levels and slightly increased astrogliosis. Deletion of Jun N‐terminal kinase (JNK)1 or JNK3 showed delayed functional recovery; deletion of JNK3 also interfered with T‐cell influx, and reduced CD44 levels. Deletion of JNK2 had no effect. Thus, neuronal c‐Jun is needed in regeneration, but JNK phosphorylation of the N‐terminus mostly appears to not be required for its function.
Jun phosphorylation required for axonal regeneration? It ain’t necessarily so.The AP‐1 transcription factor c‐Jun is critical for nerve regeneration, it is up‐regulated after injury and phosphorylated in its N‐terminus. The current study shows that specific neuronal deletion of c‐Jun gene will strongly reduce peripheral target reinnervation, functional recovery and abolish post‐traumatic neuronal cell death. However, the effects of deleting the JNKs or removing N‐terminal phosphoacceptor aminoacids are moderate, suggesting that Jun activity in regeneration is not primarily driven by a chemical modification of its N‐terminus.
Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) in western countries and Henoch-Schönlein purpura nephritis (HSPN) is the most common form of vasculitis in ...childhood. Renal biopsy findings in both nephropathies are often similar and are characterized by mesangioproliferative GN with mesangial or mesangiocapillary IgA and C3c deposits. Objectives: The aim of this study was to investigate the significance of glomerular C4d-deposition as a discriminating factor between pediatric HSPN and IgAN. Patients and Methods: We retrospectively analyzed patient records and renal biopsies from 53 pediatric patients from one single center with a median age of 10.5 years (range 2.3-18 years). Twenty-two patients suffered from IgAN and 31 from HSPN. Work-up of all renal biopsies was performed using standard protocols including immunohistochemistry for C4d. Results: Pediatric IgAN patients presented significantly more often with gross hematuria, higher serum creatinine, lower glomerular filtration rate, lower serum C3 and proteinuria and on histology less endocapillary hypercellularity compared to HSPN patients. However, the rate of glomerular C4d-positivity was not different between IgAN (36%) and HSPN (42%). Comparing all cases with positive versus negative glomerular C4d-staining, pediatric patients with glomerular C4d-positivity showed significantly lesser gross hematuria and received significantly more often cyclophosphamide. This was in line with a tendency towards more proteinuria, hypertension and renal insufficiency at last follow-up in C4d-positive compared to C4d-negative patients. Conclusion: In conclusion, in our monocentric study glomerular C4d does not differ between pediatric HSPN and IgAN, but was associated with a tendency to a more severe course of the disease that needs to be confirmed in larger multicentric studies.
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